U.S. patent number 9,321,790 [Application Number 14/409,869] was granted by the patent office on 2016-04-26 for pyrimidinone derivatives as antimalarial agents.
This patent grant is currently assigned to Sanofi. The grantee listed for this patent is SANOFI. Invention is credited to Youssef El-Ahmad, Bruno Filoche-Romme, Axel Ganzhorm, Gilbert Marciniak, Nicolas Muzet, Baptiste Ronan, Bertrand Vivet, Veronique Zerr.
United States Patent |
9,321,790 |
El-Ahmad , et al. |
April 26, 2016 |
Pyrimidinone derivatives as antimalarial agents
Abstract
The invention relates to novel pyrimidinone-based heterocyclic
compounds which are parasite growth inhibitors, having the general
formula (I) in which Y is a morpholine chosen from three bridged
morpholines, L is a bond or a linker, n=0 or 1 and R.sub.2 is a
methyl group when n=0 and a hydrogen atom when n=1. Process for the
preparation thereof and therapeutic use thereof. ##STR00001##
Inventors: |
El-Ahmad; Youssef (Paris,
FR), Filoche-Romme; Bruno (Paris, FR),
Ganzhorm; Axel (Paris, FR), Marciniak; Gilbert
(Paris, FR), Muzet; Nicolas (Paris, FR),
Ronan; Baptiste (Paris, FR), Vivet; Bertrand
(Paris, FR), Zerr; Veronique (Paris, FR) |
Applicant: |
Name |
City |
State |
Country |
Type |
SANOFI |
Paris |
N/A |
FR |
|
|
Assignee: |
Sanofi (Paris,
FR)
|
Family
ID: |
46826753 |
Appl.
No.: |
14/409,869 |
Filed: |
June 21, 2013 |
PCT
Filed: |
June 21, 2013 |
PCT No.: |
PCT/EP2013/063065 |
371(c)(1),(2),(4) Date: |
December 19, 2014 |
PCT
Pub. No.: |
WO2013/190123 |
PCT
Pub. Date: |
December 27, 2013 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20150183804 A1 |
Jul 2, 2015 |
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Foreign Application Priority Data
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Jun 22, 2012 [FR] |
|
|
12 55928 |
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
33/00 (20180101); A61P 33/06 (20180101); C09D
11/324 (20130101); C09D 127/20 (20130101); C09D
11/106 (20130101); C09D 11/322 (20130101); C09D
11/108 (20130101); C09D 161/02 (20130101); A61P
33/02 (20180101); C07D 487/04 (20130101); C09D
127/18 (20130101); A61K 31/5386 (20130101); C09D
11/30 (20130101); C07D 519/00 (20130101); C09D
181/04 (20130101); C09D 179/08 (20130101); C09D
181/06 (20130101); A61K 31/519 (20130101); A61P
33/12 (20180101); Y02A 50/411 (20180101); Y02A
50/30 (20180101); Y02A 50/423 (20180101); Y02A
50/409 (20180101); Y02A 50/414 (20180101); Y02A
50/415 (20180101) |
Current International
Class: |
A61K
31/535 (20060101); A61K 31/519 (20060101); A61K
31/5386 (20060101); C07D 519/00 (20060101); C07D
487/04 (20060101); C07D 265/36 (20060101); C07D
498/02 (20060101) |
Foreign Patent Documents
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1340761 |
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Sep 2003 |
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EP |
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1454909 |
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Sep 2004 |
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EP |
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1460076 |
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Sep 2004 |
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EP |
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2003/024949 |
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Mar 2003 |
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WO |
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2005/058908 |
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Jun 2005 |
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WO |
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2006/109081 |
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Oct 2006 |
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WO |
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2006/109084 |
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Oct 2006 |
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WO |
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2006/126010 |
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Nov 2006 |
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WO |
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2007/097981 |
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Aug 2007 |
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WO |
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2008/064244 |
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May 2008 |
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WO |
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2008/148074 |
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Dec 2008 |
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WO |
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2011/001112 |
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Jan 2011 |
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WO |
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2011/001113 |
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Jan 2011 |
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WO |
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2012/085244 |
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Jun 2012 |
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WO |
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|
Primary Examiner: Murray; Jeffrey H
Attorney, Agent or Firm: McDonnell Boehnen Hulbert &
Berghoff
Claims
The invention claimed is:
1. A compound corresponding to formula (I): ##STR00453## wherein n
is 0 or 1; Y is a bridged morpholine chosen from ##STR00454## L is
a linker --CH.sub.2--CO-- such that the carbonyl function is
attached to the substituent R.sub.1, or a (C.sub.1-C.sub.2)alkyl,
said alkyl being optionally substituted with one or more
substituents chosen from (C.sub.1-C.sub.3)alkyl and hydroxyl;
R.sub.1 is linear, branched, cyclic or partially cyclic
(C.sub.1-C.sub.5)alkyl, optionally substituted with one or more
substituents chosen from hydroxyl, aryl and trifluoromethyl,
(C.sub.3-C.sub.6)cycloalkyl, optionally substituted with hydroxyl,
aryl, optionally substituted with one or more substituents chosen
from halogen, hydroxyl, cyano, --NH.sub.2,
--NH--CO--NH--(C.sub.1-C.sub.4)alkyl, morpholine,
--SO.sub.2--(C.sub.1-C.sub.5)alkyl and (C.sub.1-C.sub.5)alkoxy,
said alkoxy being optionally substituted with one or more
substituents chosen from: halogen, hydroxyl or
(C.sub.1-C.sub.5)alkoxy, --COR.sub.3, in which R.sub.3 is
heterocycloalkyl or hydroxyl, --CONR.sub.4R.sub.4',
--NR.sub.4R.sub.4', heterocycloalkyl comprising one or two
heteroelements chosen from nitrogen and oxygen, and heteroaryl
optionally substituted with one or more substituents chosen from
halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and --NH.sub.2;
heteroaryl, comprising one or more heteroatoms chosen from
nitrogen, sulfur and oxygen, optionally substituted with one or
more substituents chosen from: halogen, (C.sub.1-C.sub.3)alkyl,
optionally substituted with one or more halogen atoms,
(C.sub.1-C.sub.5)alkoxy, optionally substituted with one or more
substituents chosen from halogen, (C.sub.3-C.sub.5)cycloalkyl, and
heteroaryl optionally substituted with one or more substituents
chosen from halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and
--NH.sub.2, and --NR.sub.5R.sub.5', wherein R.sub.5 and R.sub.5'
are independently chosen from hydrogen,
--CO.sub.2--(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.5)cycloalkyl and
linear or branched (C.sub.1-C.sub.3)alkyl, said alkyl group being
optionally substituted with one or more hydroxyl, pyridine bearing
two linked adjacent groups forming, together with the two carbons
that bear them, a heterocycle comprising a nitrogen atom and an
oxygen atom, heterocycloalkyl comprising one or more heteroatoms
chosen from oxygen and nitrogen atoms, said nitrogen atom being
optionally substituted with a substituent chosen from formyl,
acetyl and a --CO.sub.2--(C.sub.1-C.sub.4)alkyl, or
--NR.sub.6R.sub.6', wherein R.sub.6 is (C.sub.1-C.sub.5)alkyl and
R.sub.6' is (C.sub.1-C.sub.5)alkoxy, R.sub.2 is hydrogen when n is
1, and methyl when n is 0; and R.sub.4 and R.sub.4' are
independently hydrogen or (C.sub.1-C.sub.3)alkyl; in the form of
the base or of an addition salt with an acid or with a base.
2. The compound of formula (I) as claimed in claim 1, wherein n is
0 or 1; Y is bridged morpholine chosen from ##STR00455## L is a
linker --CH.sub.2--CO-- such that the carbonyl function is attached
to the substituent R.sub.1, or a (C.sub.1-C.sub.2)alkyl, optionally
substituted with one or more substituents chosen from
(C.sub.1-C.sub.3)alkyl and hydroxyl; R.sub.1 is: linear or branched
(C.sub.1-C.sub.5)alkyl, optionally substituted with one or more
substituents chosen from hydroxyl and aryl,
(C.sub.3-C.sub.6)cycloalkyl, aryl, optionally substituted with one
or more substituents chosen from halogen, hydroxyl, cyano,
--NH.sub.2, --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, morpholine,
--SO.sub.2--(C.sub.1-C.sub.5)alkyl and (C.sub.1-C.sub.5)alkoxy,
said alkoxy being optionally substituted with one or more
substituents chosen from: halogen, hydroxyl or
(C.sub.1-C.sub.5)alkoxy, --COR.sub.3, wherein R.sub.3 is
heterocycloalkyl or hydroxyl, --CONR.sub.4R.sub.4',
--NR.sub.4R.sub.4', heterocycloalkyl comprising one or two
heteroelements chosen from nitrogen and oxygen, and heteroaryl
optionally substituted with one or more substituents chosen from
halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and --NH.sub.2;
heteroaryl, comprising one or more heteroatoms chosen from
nitrogen, sulfur and oxygen, optionally substituted with one or
more substituents chosen from: halogen, (C.sub.1-C.sub.3)alkyl,
optionally substituted with one or more halogen,
(C.sub.1-C.sub.5)alkoxy, optionally substituted with one or more
substituents chosen from halogen, (C.sub.3-C.sub.5)cycloalkyl, and
heteroaryl optionally substituted with one or more substituents
chosen from halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and
--NH.sub.2, and --NR.sub.5R.sub.5', wherein R.sub.5 and R.sub.5'
are independently chosen from hydrogen,
--CO.sub.2--(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.5)cycloalkyl and
linear or branched (C.sub.1-C.sub.3)alkyl, said alkyl group being
optionally substituted with one or more hydroxyl, pyridine bearing
two linked adjacent groups forming, together with the two carbons
that bear them, a heterocycle comprising a nitrogen atom and an
oxygen atom, heterocycloalkyl comprising one or more heteroatoms
chosen from oxygen and nitrogen atoms, said nitrogen atom being
optionally substituted with a substituent chosen from formyl and
acetyl, or --NR.sub.6R.sub.6', wherein R.sub.6 is
(C.sub.1-C.sub.5)alkyl and R.sub.6' is (C.sub.1-C.sub.5)alkoxy,
R.sub.2 is hydrogen when n is 1, and methyl when n is 0; and
R.sub.4 and R.sub.4' are independently hydrogen or
(C.sub.1-C.sub.3)alkyl; in the form of the base or of an addition
salt with an acid or with a base.
3. The compound of formula (I) as claimed in claim 1, wherein Y is
bridged morpholine (a) ##STR00456## in the form of the base or of
an addition salt with an acid or with a base.
4. The compound of formula (I) as claimed in claim 1, wherein n is
0 or 1; Y is bridged morpholine (a) ##STR00457## L is a linker
--CH.sub.2--CO-- such that the carbonyl function is attached to the
substituent R.sub.1, or (C.sub.1-C.sub.2)alkyl, wherein the alkyl
is optionally substituted with one or more (C.sub.1-C.sub.3)alkyl;
R.sub.1 is linear, branched, cyclic or partially cyclic
(C.sub.1-C.sub.5)alkyl, optionally substituted with one or more
substituents chosen from hydroxyl, aryl, trifluoromethyl and
(C.sub.3-C.sub.6)cycloalkyl, (C.sub.3-C.sub.6)cycloalkyl,
optionally substituted with hydroxyl, aryl, optionally substituted
with one or more substituents chosen from halogen, hydroxyl,
--NH.sub.2, --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, morpholine,
--SO.sub.2--(C.sub.1-C.sub.5)alkyl and (C.sub.1-C.sub.5)alkoxy,
said alkoxy being optionally substituted with one or more
substituents chosen from: halogen, hydroxyl or
(C.sub.1-C.sub.5)alkoxy, --COR.sub.3, wherein R.sub.3 is
heterocycloalkyl or hydroxyl, heterocycloalkyl comprising one or
two heteroelements chosen from nitrogen and oxygen, and heteroaryl
optionally substituted with one or more substituents chosen from
halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and --NH.sub.2;
heteroaryl, comprising one or more heteroatoms chosen from
nitrogen, sulfur and oxygen, optionally substituted with one or
more substituents chosen from: halogen, (C.sub.1-C.sub.3)alkyl
optionally substituted with one or more halogen,
(C.sub.1-C.sub.5)alkoxy group, optionally substituted with one or
more substituents chosen from halogen, (C.sub.3-C.sub.5)cycloalkyl,
heteroaryl optionally substituted with one or more substituents
chosen from halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and
--NH.sub.2, and --NR.sub.5R.sub.5', wherein R.sub.5 and R.sub.5'
are independently chosen from hydrogen,
--CO.sub.2--(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.5)cycloalkyl and
linear or branched (C.sub.1-C.sub.3)alkyl, said alkyl group being
optionally substituted with one or more hydroxyl, pyridine bearing
two linked adjacent groups forming, together with the two carbons
that bear them, a heterocycle comprising a nitrogen atom and an
oxygen atom, heterocycloalkyl comprising one or more heteroatoms
chosen from oxygen and nitrogen atoms, said nitrogen atom being
optionally substituted with a substituent chosen from formyl,
acetyl and a --CO.sub.2--(C.sub.1-C.sub.4)alkyl, or
--NR.sub.6R.sub.6', wherein R.sub.6 is (C.sub.1-C.sub.5)alkyl and
R.sub.6' is (C.sub.1-C.sub.5)alkoxy, R.sub.2 is hydrogen when n is
1, and methyl when n is 0; and R.sub.4 and R.sub.4' are
independently hydrogen or (C.sub.1-C.sub.3)alkyl; in the form of
the base or of an addition salt with an acid or with a base.
5. The compound of formula (I) as claimed in claim 1, wherein n is
0 or 1; Y is bridged morpholine (a) ##STR00458## L is a linker
--CH.sub.2--CO-- such that the carbonyl function is attached to the
substituent R.sub.1, or (C.sub.1-C.sub.2)alkyl, wherein the alkyl
is optionally substituted with one or more (C.sub.1-C.sub.3)alkyl;
R.sub.1 is linear, branched, cyclic or partially cyclic
(C.sub.1-C.sub.5)alkyl, optionally substituted with one or more
substituents chosen from hydroxyl and aryl,
(C.sub.3-C.sub.6)cycloalkyl, aryl, optionally substituted with one
or more substituents chosen from halogen, hydroxyl, --NH.sub.2,
--NH--CO--NH--(C.sub.1-C.sub.4)alkyl, morpholine,
--SO.sub.2--(C.sub.1-C.sub.5)alkyl and (C.sub.1-C.sub.5)alkoxy,
said alkoxy being optionally substituted with one or more
substituents chosen from: halogen, hydroxyl or
(C.sub.1-C.sub.5)alkoxy, --COR.sub.3, wherein R.sub.3 is
heterocycloalkyl or hydroxyl, heterocycloalkyl comprising one or
two heteroelements chosen from nitrogen and oxygen, and heteroaryl
optionally substituted with one or more substituents chosen from
halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and --NH.sub.2;
heteroaryl, comprising one or more heteroatoms chosen from
nitrogen, sulfur and oxygen, optionally substituted with one or
more substituents chosen from: halogen, (C.sub.1-C.sub.3)alkyl
optionally substituted with one or more halogen,
(C.sub.1-C.sub.5)alkoxy, optionally substituted with one or more
substituents chosen from halogen, (C.sub.3-C.sub.5)cycloalkyl, and
heteroaryl optionally substituted with one or more substituents
chosen from halogen, (C.sub.1-C.sub.3)alkyl, hydroxyl and
--NH.sub.2, and --NR.sub.5R.sub.5', wherein R.sub.5 and R.sub.5'
are independently chosen from hydrogen,
--CO.sub.2--(C.sub.1-C.sub.3)alkyl, (C.sub.3-C.sub.5)cycloalkyl and
linear or branched (C.sub.1-C.sub.3)alkyl, said alkyl group being
optionally substituted with one or more hydroxyl, pyridine bearing
two linked adjacent groups forming, together with the two carbons
that bear them, a heterocycle comprising a nitrogen atom and an
oxygen atom, heterocycloalkyl comprising one or more heteroatoms
chosen from oxygen and nitrogen atoms, said nitrogen atom being
optionally substituted with a substituent chosen from formyl and
acetyl, or --NR.sub.6R.sub.6', wherein R.sub.6 is
(C.sub.1-C.sub.5)alkyl and R.sub.6' is (C.sub.1-C.sub.5)alkoxy,
R.sub.2 is hydrogen when n is 1, and methyl when n is 0; and
R.sub.4 and R.sub.4' are independently hydrogen or
(C.sub.1-C.sub.3)alkyl; in the form of the base or of an addition
salt with an acid or with a base.
6. The compound of formula (I) as claimed in claim 1, wherein n is
0 or 1; Y is bridged morpholine chosen from (b) and (c)
##STR00459## L is a linker --CH.sub.2--CO-- such that the carbonyl
function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, wherein the alkyl is optionally substituted
with a hydroxyl group; R.sub.1 is linear or branched
(C.sub.1-C.sub.5)alkyl, optionally substituted with aryl, aryl,
optionally substituted with one or more substituents chosen from
halogen, hydroxyl and (C.sub.1-C.sub.5)alkoxy, said alkoxy being
optionally substituted with one or more substituents chosen from:
--CONR.sub.4R.sub.4', --NR.sub.4R.sub.4', and heteroaryl comprising
one or more heteroatoms chosen from nitrogen, sulfur and oxygen,
optionally substituted with one or more (C.sub.1-C.sub.3)alkyl,
optionally substituted with one or more halogen, R.sub.2 is
hydrogen when n is 1, and methyl when n is 0; and R.sub.4 and
R.sub.4' are independently hydrogen or (C.sub.1-C.sub.3)alkyl; in
the form of the base or of an addition salt with an acid or with a
base.
7. The compound as claimed in claim 1, wherein the linker L is
--CH.sub.2--CO, in the form of the base or of an addition salt with
an acid or with a base.
8. The compound as claimed in claim 1, wherein n is 1, in the form
of the base or of an addition salt with an acid or with a base.
9. The compound as claimed in claim 1, wherein n is 0, in the form
of the base or of an addition salt with an acid or with a base.
10. The compound as claimed in claim 1, wherein R.sub.1 is
heteroaryl, in the form of the base or of an addition salt with an
acid or with a base.
11. The compound as claimed in claim 1, wherein R.sub.1 is
heterocycloalkyl comprising one or more heteroatoms chosen from
oxygen and nitrogen atoms, said nitrogen atom being optionally
substituted with a substituent chosen from formyl, acetyl and a
--CO.sub.2--(C.sub.1-C.sub.4)alkyl, in the form of the base or of
an addition salt with an acid or with a base.
12. A compound of formulae i, N, Q or S: ##STR00460## wherein n is
0 or 1; Y is a bridged morpholine chosen from ##STR00461## and
R.sub.2 is hydrogen when n is 1, and methyl when n is 0.
13. The compound as claimed in claim 1, wherein the compound is:
(8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-yl-
ethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one;
(8S)-9-[2-(6-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(8S)-9-[2-(6-Methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one;
(8S)-9-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylet-
hyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
1-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-
-a]pyrimidin-5-one;
2-(S)-Methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a-
]pyrimidin-5-one;
(8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one;
(S)-1-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-methyl-7-(1S,4S)-2-oxa-5-a-
zabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]p-
yrimidin-5-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
2-Methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-pyrid-3-ylethy-
l)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;
(8S)-9-{2-[6-(2-Hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one;
2-Methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5--
azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[-
1,2-a]pyrimidin-5-one;
2-Methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidi-
n-5-one;
2-Methyl-1-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5--
azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[-
1,2-a]pyrimidin-5-one;
(8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one;
(8S)-9-[2-(4-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]-
pyrimidin-4-one;
2-Methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3--
ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one;
(8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one;
1-Ethyl-3-{4-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-
-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phe-
nyl}urea;
1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin--
1-yl)ethyl]phenyl}urea;
(8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one;
2-Methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one;
(8S)-9-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one;
1-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2--
a]pyrimidin-5-one;
(8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
1-(3,3-Dimethyl-2-oxobutyl)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one;
(8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5--
azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,-
2-a]pyrimidin-4-one;
1-[2-(4-Aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-o-
ne;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(6-triflu-
oromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,-
2-a]pyrimidin-4-one;
(8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(1S,4-
S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(6-Ethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one;
(8S)-9-[2-(6-Amino-4,5-dimethylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)--
2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyr-
imido[1,2-a]pyrimidin-4-one;
(S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one;
(8S)-9-[2-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1-
S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahy-
dropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one;
(S)-9-[2-(3,4-Difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]-
pyrimidin-4-one;
(8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one;
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]benzonitrile;
(8S)-9-[2-(4-Methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one;
(8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one;
(8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one;
(8S)-9-[2-(3-Methylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5--
azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,-
2-a]pyrimidin-4-one;
(8S)-9-(2-Benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(8S)-9-[2-(2,4-Difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one;
(8S)-9-(3-Ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2-
.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin--
4-one;
(8S)-9-(3-Hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one;
(8S)-9-(1-Methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one;
(8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S-
,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahyd-
ropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(3,5-Dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(8S)-9-(2-Ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
3-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]benzonitrile;
(8S)-9-(3-Methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
{5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamic acid ethyl ester;
{5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamic acid methyl ester;
(8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrim-
idin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2-trifluoro-
methylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one;
(8S)-9-(2-Benzo[1,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydrop-
yran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one;
(8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)--
2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyr-
imido[1,2-a]pyrimidin-4-one;
(8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxyl)phenyl]-2-oxoethyl}-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one;
(8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one;
(8S)-9-(2-Cyclopropyl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-ylet-
hyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabic-
yclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one;
N,N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)--
5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}-
phenoxy)acetamide;
(8S)-9-[(S)-2-(4-Fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabi-
cyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
(2S)-1-[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oc-
t-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8-trif-
luoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(2S)-1-{2-[4-(2-Dimethylaminoethoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-az-
abicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one;
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-
-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;
(S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(3-phenylpropyl)-2-t-
rifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;
(S)-1-{2-[4-(3-Dimethylaminopropoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-az-
abicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one;
(2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1-
]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one;
(8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl-
)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3-azabicyclo-
[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one;
(8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e;
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluo-
romethylmethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-2-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-(1-Difluoromethyl-1H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2-
.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin--
4-one;
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-3-yleth-
yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(S)-9-[2-(1-Acetylpiperid-4-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-o-
ne;
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluo-
romethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine--
1-carbaldehyde;
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]piperidine-1--
carboxylic acid ethyl ester;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-
-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran--
4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-
-one;
(8S)-9-(1-Acetylpiperid-4-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2-
.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin--
4-one;
4-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluo-
romethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine--
1-carbaldehyde;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hy-
droxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluoro-3-hy-
droxy-3-trifluoromethylbutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3-azabicycl-
o[3.2.1]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicycl-
o[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(1-Hydroxycyclopentyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one;
(8S)-9-(1-Hydroxycyclopentylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.-
1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-
-one;
(8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one;
(8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one;
(8S)-9-(1-Hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one;
(8S)-9-[2-(1-Hydroxycyclopropyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one;
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one;
(8S)-9-[2-(4-Methanesulfonylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one;
(8S)-9-Isoquinolin-5-ylmethyl-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-y-
l-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one;
(8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e;
(8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one;
N-Methoxy-N-methyl-2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6--
oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acet-
amide;
(8S)-9-(2-Imidazo[1,2-a]pyrid-6-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one;
(8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one;
(S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1-
,2-a]pyrimidin-4-one;
(8S)-9-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one;
(8S)-9-{2-[4-(2-Dimethylaminoethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one;
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]piperidine-1--
carbaldehyde; or
(8S)-9-[2-(1-Acetylpiperid-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one; in the form of the base or of an addition salt with an
acid or with a base.
14. A pharmaceutical composition, comprising a compound as claimed
in claim 1, or a pharmaceutically acceptable salt of this compound,
and at least one pharmaceutically acceptable excipient.
15. A process for preparing a compound of formula (I) as claimed in
claim 1, comprising the reaction of a compound of formula E:
##STR00462## wherein n is 0 or 1 and R.sub.2 is hydrogen when n=1,
or methyl when n=0; with a bridged morpholine Y, chosen from (a),
(b) and (c) as defined in claim 1; to obtain a compound of formula
i: ##STR00463## and the alkylation reaction by addition to I of a
compound of formula J=R.sub.1-L-Lg wherein R.sub.1 and L are as
defined in claim 1 and Lg is a leaving group.
16. A process for preparing a compound of formula (I) as claimed in
claim 1, comprising the alkylation reaction of a compound of
formula E: ##STR00464## wherein n is 0 or 1 and R.sub.2 is a
hydrogen atom when n=1 or a methyl group when n=0; by addition of a
compound of formula J=R.sub.1-L-Lg wherein R.sub.1 and L are as
defined in claim 1 and Lg is a leaving group; to obtain a compound
of formula K: ##STR00465## wherein R.sub.1, R.sub.2, L and n are as
defined in claim 1, and a reaction on a compound K with a compound
of formula Y being a bridged morpholine chosen from (a), (b) and
(c) as defined in claim 1.
17. A process for preparing a compound of formula (I) as claimed in
claim 1, wherein the linker L is ethyl, R.sub.1 is linear or
branched (C.sub.1-C.sub.5)alkyl substituted with hydroxyl, Y is a
bridged morpholine chosen from (a), (b) and (c) as defined in claim
1, n is 1 or 0, and R.sub.2 is hydrogen when n=1, and methyl when
n=0, comprising a Michael addition reaction of a compound of
formula E: ##STR00466## wherein n is 0 or 1 and R.sub.2 is hydrogen
when n=1, or methyl when n=0; on a compound of formula
M=CH.sub.2.dbd.CH.sub.2--CO.sub.2Alkyl, to obtain a compound of
formula N: ##STR00467## wherein n is 0 or 1 and R.sub.2 is hydrogen
when n=1, or methyl when n=0, and Y is a bridged morpholine chosen
from (a), (b) and (c) as defined in claim 1; and a reaction of
alkyl on a compound of formula N with a compound of formula
O.dbd.Z--Mg--X wherein Z is linear or branched alkyl and X is
halogen.
18. A process for preparing a compound of formula (I) as claimed in
claim 1, wherein the linker L is methyl, R.sub.1 is linear or
branched (C.sub.1-C.sub.5)alkyl substituted with hydroxyl, Y is a
bridged morpholine chosen from (a), (b) and (c) as defined in claim
1, n is 1 or 0, and R.sub.2 is hydrogen when n=1, and methyl when
n=0, comprising an addition reaction of a compound of formula E:
##STR00468## wherein n is 0 or 1 and R.sub.2 is hydrogen when n=1,
or methyl when n=0, with a compound of formula
P.dbd.X--CH.sub.2--CO.sub.2Alkyl wherein X is halogen; to obtain a
compound of formula Q: ##STR00469## wherein Y is a bridged
morpholine chosen from (a), (b) and (c), n is 0 or 1 and R.sub.2 is
hydrogen when n=1, or methyl when n=0; and an alkylation reaction
on a compound of formula Q with a compound of formula
O.dbd.Z--Mg--X, wherein Z is linear or branched alkyl and X is
halogen.
19. A process for preparing a compound of formula (I) as claimed in
claim 1, wherein the linker L is methyl, R.sub.1 is
--NR.sub.6R.sub.6', wherein R.sub.6 is alkyl and R.sub.6' is
alkoxy, or R.sub.6 and R.sub.6' together form a monocyclic or
bicyclic heterocycloalkyl, Y is a bridged morpholine chosen from
(a), (b) and (c) as defined in claim 1, n is 1 or 0, and R.sub.2 is
hydrogen when n=1, and methyl when n=0, comprising a hydrolysis
reaction of a compound of formula Q: ##STR00470## wherein Y is a
bridged morpholine chosen from (a), (b) and (c), n is 0 or 1 and
R.sub.2 is hydrogen when n=1, or methyl when n=0, to obtain a
compound of formula S: ##STR00471## wherein Y is a bridged
morpholine chosen from (a), (b) and (c) as defined in claim 1, n is
1 or 0 and R.sub.2 is hydrogen when n=1, or methyl when n=0; and a
coupling reaction between a compound of formula S and a compound of
formula HNR.sub.6R.sub.6' wherein R.sub.6 is alkyl and R.sub.6' is
alkoxy, or R.sub.6 and R.sub.6' together form a monocyclic or
bicyclic heterocycloalkyl.
20. A method for treating parasite-induced malaria, the method
comprising administrating to a patient in need thereof an effective
amount of a compound according to claim 1.
21. A method for the treatment of malaria induced by a species of
Plasmodium, a species of Trypanosoma or a species of Leishmania,
the treatment of sleeping sickness, the treatment of Chagas
disease, the treatment of of leishmaniasis, or the treatment of
another parasitic infection, the method comprising administrating
to a patient in need thereof an effective amount of a compound
according to claim 1.
22. The method of claim 21, wherein the species of Plasmodium is P.
falciparum, P. vivax, P. malariae, P. ovale or P. knowlesi.
23. The method of claim 21, wherein the parasitic infection is
schistosomiasis (bilharzia), toxoplasmosis or coccidiosis.
Description
This application is a national stage application under 35 U.S.C.
.sctn.371 of International Application No. PCT/EP2013/063065, filed
Jun. 21, 2013, which claims priority of France Application No.
1255928 filed on Jun. 22, 2012.
The present invention relates to pyrimidinone derivatives, and to
the preparation and therapeutic use thereof.
Malaria is one of the prime causes of infection-mediated mortality
worldwide. Infection with the parasite of the type Plasmodium
falciparum affects close to 225 million people, causes more than
781 000 deaths annually and predominantly concerns children under 5
years old. The substantial return of the disease observed in recent
years is due to several factors, including: the vectors, namely
anopheles, which become resistant to the standard cheap
insecticides, the increase in the population in the at-risk zones
and, mainly, the resistance of numerous strains of Plasmodium
falciparum, the parasite responsible for the mortal forms of the
disease, to the medicaments conventionally used, such as
chloroquine and mefloquine. Since 2001, artemisinin and derivatives
thereof have been considered by the World Health Organization as
the treatment of choice for Plasmodium falciparum-mediated
uncomplicated malaria. However, clear signs of development of
resistance to artemisinins have been observed.
The propagation of resistance among Plasmodium strains, in
particular P. falciparum, towards the majority of the antimalarial
drugs demonstrates the urgent need to develop novel compounds
having a novel mode of action thus enabling a decrease of the risk
of cross-resistance. Human kinases are valid targets in the
treatment of numerous pathologies and the kinome of P. falciparum
has been proposed as a reservoir of novel targets for the
development of novel medicaments, which have not yet been explored
in the treatment of malaria (Doerig and Meijer (2007) Expert Opin.
Ther. Targets 11, 279-290).
The kinome of Plasmodium falciparum is composed of 64 kinases, some
of which are orthologous to human kinases (Ward et al. (2004) BMC
Genomics 5,79). Following this orthologous approach, a group of
CF.sub.3-pyrimidinone derivatives, which are active on human
phosphatidylinositol-3-kinases, has been identified as being
parasite growth inhibitors in human erythrocytes. Moreover, a
plasmodial phosphatidylinositol-3-kinase, known as PfPI3K, has
recently been identified, and the existence of a relationship
between this kinase and human phosphatidylinositol kinases has been
demonstrated (Vaid et al. (2010) Blood 115, 2500-2507). PfPI3K
intervenes in the mechanism of endocytosis and in trafficking the
host hemoglobin and as such plays an important role in maintaining
the parasite growth in the infected human erythrocyte. It might
thus be thereby deduced that the plasmodial kinase PfPI3K would be
a target for the compounds of the present invention.
Human PI3Ks play a major role in signaling and traffic in human
cells (Engelman et al. (2006) Nature Rev. Genetics 7, 606-619). The
PI3K/Akt/mTOR signaling mechanism is an essential regulator of cell
life, cell proliferation and protein synthesis. The insulin
signaling pathway via the PI3K/Akt axis involving class 1A of PI3Ks
(PI3K.alpha. and .beta.) is essential in glucose homeostasis.
Downstream attenuation of insulin receptor signaling plays an
important role in the development of type-2 diabetes. The other
isoforms of class I PI3K, PI3K.gamma. and PI3K.delta., are involved
in the immune function and inflammation (Ihle and Povis (2010)
Current Opinion in Drug Discovery & Development 13, 41-49).
Inhibition of PI3K.alpha. or PI3K.delta. in mice results in
embryonic lethality (Bi et al. (1999) J. Biol. Chem. 274,
10963-10968; Bi et al. (2002) Mamm Genome 13, 169-172). Moreover,
mice showing a deficiency in PI3K.gamma. or PI3K.delta. show
deficiences in immune functions (Okkenhaug et al. (2002) Science
297, 1031-1034). A summary of the potential and observable side
effects of PI3K inhibition may be found in the articles by Cully et
al. ((2006) Nature Rev. 6, 184-192) and Ihle and Powis ((2009) Mol.
Cancer Ther. 8, 1-9).
Inhibition of class III PI3K, PIK3C3/VPS34, may also give rise to
adverse side effects such as rapid neuron degeneration in mice
following the conditional suppression of VPS34 in the sensory
neurons (Zhou et al. (2010) PNAS 107, 9424-9429).
In summary, non-limiting examples that may be mentioned of
potential side effects due to PI3K inhibition in man include
metabolic disturbances associated with inhibition of insulin
signaling with an increase of blood glucose, reduction of insulin
sensitivity, diabetes, deregulation of the cerebral functions with
the potential for inducing symptoms of schizophrenia and of
Parkinson's disease, and neurodegeneration, and also
immunosuppression. It should also be noted that nausea, diarrhea,
tiredness, vomiting, skin eruptions and liver damage have been
observed during clinical studies with inhibitors of the PI3K/mTOR
axis.
On the basis of these observations, it is obvious that inhibiting
human PI3K lipid kinases may have highly undesirable effects and
should be avoided when the lipid kinome of Plasmodium is targeted
for the treatment of malaria.
CF.sub.3-pyrimidinone derivatives have been described in patent
applications WO 2011/001112 and WO 2011/001113 for the preparation
of medicaments for treating various cancers and also for treating
parasitic diseases such as malaria. These compounds are described
as inhibitors of human PI3Ks.
The compounds of the present invention have the advantage, although
being derived from inhibitors of human PI3K and in particular
PI3K.alpha., they do not inhibit this class of human kinases, while
nonetheless remaining inhibitors of parasite growth.
Similar kinomes are present in all species of Plasmodium, such as
P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The
compounds of the invention may thus be useful in the treatment of
malaria induced by all the parasites mentioned above. In addition,
the kinases are found in other parasites, such as Trypanosoma (for
example T. brucei, T. cruzei) and Leishmania (for example L. major,
L. donovani). The compounds of the invention may thus be used in
the treatment of sleeping sickness, Chagas disease, the various
forms of leishmaniasis and other parasitic infections.
Other parasites, such as schistosomes, toxoplasms and Eimeria, also
use kinases for their cell regulation. Consequently, the compounds
of the present invention may be useful in the treatment of
schistosomiasis (bilharzia), toxoplasmosis and coccidiosis.
The present invention relates to compounds corresponding to formula
(I):
##STR00002##
in which: n represents 0 or 1; Y represents a bridged morpholine
chosen from
##STR00003## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or a
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more substituents chosen from a (C.sub.1-C.sub.3)alkyl
group and a hydroxyl group; R.sub.1 represents: a linear, branched,
cyclic or partially cyclic (C.sub.1-C.sub.5)alkyl group, optionally
substituted with one or more substituents chosen from a hydroxyl
group, an aryl group, a trifluoromethyl group and a
(C.sub.3-C.sub.5)cycloalkyl group, a (C.sub.3-C.sub.6)cycloalkyl
group, optionally substituted with a hydroxyl group, an aryl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a hydroxyl group, a cyano group, an --NH.sub.2 group,
a urea group of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a
morpholine group, a group of formula
--SO.sub.2--(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)alkoxy
group, said alkoxy being optionally substituted with one or more
substituents chosen from: a halogen atom, a hydroxyl group or a
(C.sub.1-C.sub.5)alkoxy group, a group --COR.sub.3, in which
R.sub.3 represents a substituent chosen from a heterocycloalkyl
group and a hydroxyl group, a group --CONR.sub.4R.sub.4' in which
R.sub.4 and R.sub.4' are as defined below, a group
--NR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a heterocycloalkyl group comprising one or two
heteroelements chosen from a nitrogen atom and an oxygen atom, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group; a heteroaryl
group, comprising one or more heteroatoms chosen from a nitrogen
atom, a sulfur atom and an oxygen atom, optionally substituted with
one or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group, optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5
and R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, a heterocycloalkyl group comprising one or more
heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen
atom being optionally substituted with a substituent chosen from a
formyl group, an acetyl group and a
--CO.sub.2--(C.sub.1-C.sub.4)alkyl group, a group
--NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6' which are
different, represent a (C.sub.1-C.sub.5)alkyl group and a
(C.sub.1-C.sub.5)alkoxy group, R.sub.2 represents a hydrogen atom
when n represents 1 and a methyl group when n represents 0; R.sub.4
and R.sub.4', independently, which may be identical or different,
represent a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, in the
form of the base or of an addition salt with an acid or with a
base.
The compounds of formula (I) can comprise one or more asymmetric
carbon atoms. They can therefore exist in the form of enantiomers
or diastereoisomers. These enantiomers, diastereoisomers and also
mixtures thereof, including racemic mixtures, are part of the
invention.
The compounds of formula (I) may exist in the form of bases or
salified with acids or bases, especially pharmaceutically
acceptable acids or bases. Such addition salts are part of the
invention.
These salts are prepared with pharmaceutically acceptable acids,
but salts of other acids that are of use, for example, for
purifying or isolating the compounds of formula (I) also form part
of the invention. In particular, use will be made in the context of
the invention of the hydrogen chloride salt.
In the context of the present invention, and unless otherwise
mentioned in the text: a halogen atom: a fluorine atom, a chlorine
atom, a bromine atom or an iodine atom; in particular, the halogen
atom is a fluorine atom; an alkyl group: unless otherwise mentioned
in the text, a linear or branched saturated aliphatic group
containing from 1 to 5 carbons. Examples that may be mentioned
include methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
tert-butyl and pentyl groups; a partially cyclic
(C.sub.1-C.sub.5)alkyl group: unless otherwise mentioned in the
text, a linear saturated aliphatic group substituted with a
(C.sub.3-C.sub.4)cycloalkyl group. Examples that may be mentioned
include methylcyclopropyl, methylcyclobutyl and ethylcyclopropyl
groups; a cycloalkyl group: a cyclic (C.sub.3-C.sub.6)alkyl group.
Examples that may be mentioned include cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl groups; an alkoxy group: a radical
--O-alkyl in which the alkyl group is as defined previously, in
particular the alkyl group is a methyl or ethyl; an aryl group: a
cyclic aromatic group comprising between 5 and 6 carbon atoms. An
example of an aryl group that may be mentioned is the phenyl group;
a heteroaryl group: a monocyclic or bicyclic aromatic group
comprising between 2 and 9 carbon atoms and comprising between 1
and 4 heteroatoms, such as nitrogen, oxygen or sulfur. In
particular, the bicyclic aromatic groups comprise a phenyl group.
Examples of monocyclic heteroaryl groups that may be mentioned
include imidazolyl, pyrimidyl, isoxazolyl, thiazolyl, isothiazolyl,
pyridyl, pyrazolyl, oxazolyl and 1,2,4-oxadiazolyl groups. Examples
of bicyclic heteroaryl groups that may be mentioned include
1H-indazolyl, benzo[1,2,3]thiadiazolyl, benzo[1,2,5]thiadiazolyl,
benzothiophenyl, imidazo[1,2-a]pyridyl, quinolinyl and
isoquinolinyl groups; a heterocycloalkyl: a monocyclic or bicyclic
alkyl group comprising from 4 to 8 atoms, 1 or 2 of which are
heteroatoms, chosen from an oxygen atom and a nitrogen atom.
Examples of monocyclic heterocycloalkyl groups that may especially
be mentioned include piperidyl, morpholinyl and tetrahydropyranyl
groups, and examples of bicyclic heterocycloalkyl groups that may
be mentioned include groups of bridged morpholine type:
8-oxa-3-azabicyclo[3.2.1]oct-3-yl,
3-oxa-8-azabicyclo[3.2.1]oct-8-yl.
Among the compounds of the invention, mention may be made of a
first subgroup of compounds corresponding to formula (I):
##STR00004##
in which: n represents 0 or 1, and/or Y represents a bridged
morpholine chosen from
##STR00005##
and/or L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or a
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more substituents chosen from a (C.sub.1-C.sub.3)alkyl
group and a hydroxyl group, and/or R.sub.1 represents: a linear,
branched, cyclic or partially cyclic (C.sub.1-C.sub.5)alkyl group,
optionally substituted with one or more substituents chosen from a
hydroxyl group, an aryl group, a trifluoromethyl group and a
(C.sub.3-C.sub.5)cycloalkyl group, a (C.sub.3-C.sub.6)cycloalkyl
group, optionally substituted with a hydroxyl group, an aryl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a hydroxyl group, a cyano group, an --NH.sub.2 group,
a urea group of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a
morpholine group, a group of formula
--SO.sub.2--(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)alkoxy
group, said alkoxy being optionally substituted with one or more
substituents chosen from: a halogen atom, a hydroxyl group or a
(C.sub.1-C.sub.5)alkoxy group, a group --COR.sub.3, in which
R.sub.3 represents a substituent chosen from a heterocycloalkyl
group and a hydroxyl group, a group --CONR.sub.4R.sub.4' in which
R.sub.4 and R.sub.4' are as defined below, a group
--NR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a heterocycloalkyl group comprising one or two
heteroelements chosen from a nitrogen atom and an oxygen atom, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group; a heteroaryl
group, comprising one or more heteroatoms chosen from a nitrogen
atom, a sulfur atom and an oxygen atom, optionally substituted with
one or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group, optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5
and R.sub.5' independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, a heterocycloalkyl group comprising one or more
heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen
atom being optionally substituted with a substituent chosen from a
formyl group, an acetyl group and a
--CO.sub.2--(C.sub.1-C.sub.4)alkyl group, a group
--NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6' which are
different, represent a (C.sub.1-C.sub.5)alkyl group and a
(C.sub.1-C.sub.5)alkoxy group, and/or R.sub.2 represents a hydrogen
atom when n represents 1 and a methyl group when n represents 0,
and/or R.sub.4 and R.sub.4', independently, which may be identical
or different, represent a hydrogen atom or a (C.sub.1-C.sub.3)alkyl
group, in the form of the base or of an addition salt with an acid
or with a base.
Among the compounds of the present invention, mention may be made
of a second subgroup of compounds of formula (I) in which: n
represents 0 or 1; Y represents a bridged morpholine chosen
from
##STR00006## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or a
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more substituents chosen from a (C.sub.1-C.sub.3)alkyl
group and a hydroxyl group; R.sub.1 represents: a linear or
branched (C.sub.1-C.sub.5) alkyl group, optionally substituted with
one or more substituents chosen from a hydroxyl group and an aryl
group, a group (C.sub.3-C.sub.6)cycloalkyl, an aryl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a hydroxyl group, a cyano group, an --NH.sub.2 group,
a urea group of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a
morpholine group, a group of formula
--SO.sub.2--(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)alkoxy
group, said alkoxy being optionally substituted with one or more
substituents chosen from: a halogen atom, a hydroxyl group or a
(C.sub.1-C.sub.5)alkoxy group, a group --COR.sub.3, in which
R.sub.3 represents a substituent chosen from a heterocycloalkyl
group and a hydroxyl group, a group --CONR.sub.4R.sub.4' in which
R.sub.4 and R.sub.4' are as defined below, a group
--NR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a heterocycloalkyl group comprising one or two
heteroelements chosen from a nitrogen atom and an oxygen atom, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group, a heteroaryl
group, comprising one or more heteroatoms chosen from a nitrogen
atom, a sulfur atom and an oxygen atom, optionally substituted with
one or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group, optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5
and R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, a heterocycloalkyl group comprising one or more
heteroatoms chosen from oxygen and nitrogen atoms, said nitrogen
atom being optionally substituted with a substituent chosen from a
formyl group and an acetyl group, a group --NR.sub.6R.sub.6' in
which R.sub.6 and R.sub.6' which are different, represent a
(C.sub.1-C.sub.5)alkyl group and a (C.sub.1-C.sub.5)alkoxy group,
R.sub.2 represents a hydrogen atom when n represents 1 and a methyl
group when n represents 0; R.sub.4 and R.sub.4', independently,
which may be identical or different, represent a hydrogen atom or a
(C.sub.1-C.sub.3)alkyl group, in the form of the base or of an
addition salt with an acid or with a base.
Among the compounds of the present invention, mention may be made
of a third subgroup of compounds of formula (I) in which: n
represents 0 or 1; Y represents a bridged morpholine (a)
##STR00007## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more substituents chosen from a (C.sub.1-C.sub.3)alkyl
group and a hydroxyl group; R.sub.1 represents: a linear, branched,
cyclic or partially cyclic (C.sub.1-C.sub.5)alkyl group, optionally
substituted with one or more substituents chosen from a hydroxyl
group, an aryl group, a trifluoromethyl group and a
(C.sub.3-C.sub.5)cycloalkyl group, a (C.sub.3-C.sub.6)cycloalkyl
group, optionally substituted with a hydroxyl group, an aryl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a hydroxyl group, an --NH.sub.2 group, a urea group
of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a morpholine
group, a group of formula --SO.sub.2--(C.sub.1-C.sub.5)alkyl, a
(C.sub.1-C.sub.5)alkoxy group, said alkoxy being optionally
substituted with one or more substituents chosen from: a halogen
atom, a hydroxyl group or a (C.sub.1-C.sub.5)alkoxy group, a group
--COR.sub.3, in which R.sub.3 represents a substituent chosen from
a heterocycloalkyl group and a hydroxyl group, a group
--CONR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a group --NR.sub.4R.sub.4, in which R.sub.4 and R.sub.4' are
as defined below, a heterocycloalkyl group comprising one or two
heteroelements chosen from a nitrogen atom and an oxygen atom, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group, a heteroaryl
group, comprising one or more heteroatoms chosen from a nitrogen
atom, a sulfur atom and an oxygen atom, optionally substituted with
one or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group, optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5
and R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, a heterocycloalkyl group comprising one or more
heteroatoms chosen from oxygen and nitrogen atoms, in particular a
morpholinyl group, a bridged morpholinyl group, a tetrahydropyranyl
group and a piperidyl group, said nitrogen atom being optionally
substituted with a substituent chosen from a formyl group, an
acetyl group and a --CO.sub.2--(C.sub.1-C.sub.4)alkyl group, a
group --NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6', which are
different, represent a (C.sub.1-C.sub.5)alkyl group and a
(C.sub.1-C.sub.5)alkoxy group, R.sub.2 represents a hydrogen atom
when n represents 1 and a methyl group when n represents 0; R.sub.4
and R.sub.4', independently, which may be identical or different,
represent a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, in the
form of the base or of an addition salt with an acid or with a
base.
Among the compounds of the present invention, mention may be made
of a fourth subgroup of compounds of formula (I) in which: n
represents 0 or 1; Y represents a bridged morpholine (a)
##STR00008## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more substituents chosen from a (C.sub.1-C.sub.3)alkyl
group and a hydroxyl group; R.sub.1 represents: a linear or
branched (C.sub.1-C.sub.5)alkyl group, optionally substituted with
one or more substituents chosen from a hydroxyl group and an aryl
group, a (C.sub.3-C.sub.6)cycloalkyl group, an aryl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a hydroxyl group, an --NH.sub.2 group, a urea group
of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a morpholine
group, a group of formula --SO.sub.2--(C.sub.1-C.sub.5)alkyl, a
(C.sub.1-C.sub.5)alkoxy group, said alkoxy being optionally
substituted with one or more substituents chosen from: a halogen
atom, a hydroxyl group or a (C.sub.1-C.sub.5)alkoxy, a group
--COR.sub.3, in which R.sub.3 represents a substituent chosen from
a heterocycloalkyl group and a hydroxyl group, a group
--CONR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a group --NR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are
as defined below, a heterocycloalkyl group comprising one or two
heteroelements chosen from a nitrogen atom and an oxygen atom, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group; a heteroaryl
group, comprising one or more heteroatoms chosen from a nitrogen
atom, a sulfur atom and an oxygen atom, optionally substituted with
one or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group, optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5
and R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, a heterocycloalkyl group comprising one or more
heteroatoms chosen from oxygen and nitrogen atoms, in particular a
morpholinyl group, a bridged morpholinyl group and a piperidyl
group, said nitrogen atom being optionally substituted with a
substituent chosen from a formyl group and an acetyl group, a group
--NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6' which are
different, represent a (C.sub.1-C.sub.5)alkyl group and a
(C.sub.1-C.sub.5)alkoxy group, R.sub.2 represents a hydrogen atom
when n represents 1 and a methyl group when n represents 0; R.sub.4
and R.sub.4', independently, which may be identical or different,
represent a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, in the
form of the base or of an addition salt with an acid or with a
base.
Among the compounds of the present invention, mention may be made
of a fifth subgroup of compounds of formula (I) in which: n
represents 0 or 1; Y represents a bridged morpholine (a)
##STR00009## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more (C.sub.1-C.sub.3)alkyl groups; R.sub.1 represents:
a linear, branched, cyclic or partially cyclic
(C.sub.1-C.sub.5)alkyl group, in particular an isopropyl or
tert-butyl group, optionally substituted with one or more
substituents chosen from a hydroxyl group, an aryl group, a
trifluoromethyl group and a (C.sub.3-C.sub.5)cycloalkyl group, a
(C.sub.3-C.sub.6)cycloalkyl group, optionally substituted with a
hydroxyl group, an aryl group, in particular a phenyl group,
optionally substituted with one or more substituents chosen from a
halogen atom, a cyano group, an --NH.sub.2 group, a urea group of
formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a morpholine group, a
group of formula --SO.sub.2--(C.sub.1-C.sub.5)alkyl, a
(C.sub.1-C.sub.5)alkoxy group, in particular a methoxy group, said
alkoxy being optionally substituted with one or more substituents
chosen from: a halogen atom, in particular a fluorine atom, a
hydroxyl group or a (C.sub.1-C.sub.5)alkoxy group, a group
--COR.sub.3, in which R.sub.3 represents a substituent chosen from
a heterocycloalkyl group and a hydroxyl group, a heterocycloalkyl
group comprising one or two heteroelements chosen from a nitrogen
atom and an oxygen atom, in particular a morpholinyl group, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group; a heteroaryl
group, comprising one or more heteroatoms chosen from nitrogen
atoms, in particular a pyridyl group, and sulfur and oxygen atoms,
optionally substituted with one or more substituents chosen from: a
halogen atom, a (C.sub.1-C.sub.3)alkyl group optionally substituted
with one or more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group,
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl
group optionally substituted with one or more substituents chosen
from a halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl
group and an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which
R.sub.5 and R.sub.5', independently, which may be identical or
different, represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, in particular a
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group, a heterocycloalkyl
group comprising one or more heteroatoms chosen from oxygen and
nitrogen atoms, said nitrogen atom being optionally substituted
with a substituent chosen from a formyl group, an acetyl group and
a --CO.sub.2--(C.sub.1-C.sub.4)alkyl group, a group
--NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6', which are
different, represent an alkyl group and a (C.sub.1-C.sub.5)alkoxy
group, R.sub.2 represents a hydrogen atom when n represents 1 and a
methyl group when n represents 0; in the form of the base or of an
addition salt with an acid or with a base.
Among the compounds of the present invention, mention may be made
of a sixth subgroup of compounds of formula (I) in which: n
represents 0 or 1; Y represents a bridged morpholine (a)
##STR00010## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with one or more (C.sub.1-C.sub.3)alkyl groups; R.sub.1 represents:
a linear or branched (C.sub.1-C.sub.5)alkyl group, in particular an
isopropyl or tert-butyl group, optionally substituted with one or
more hydroxyl groups, a (C.sub.3-C.sub.6)cycloalkyl group, an aryl
group, in particular a phenyl group, optionally substituted with
one or more substituents chosen from a halogen atom, a cyano group,
an --NH.sub.2 group, a urea group of formula
--NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a morpholine group, a group
of formula --SO.sub.2--(C.sub.1-C.sub.5)alkyl, a
(C.sub.1-C.sub.5)alkoxy group, in particular a methoxy group, said
alkoxy being optionally substituted with one or more substituents
chosen from: a halogen atom, in particular a fluorine atom, a
hydroxyl group or a (C.sub.1-C.sub.5)alkoxy, a group --COR.sub.3,
in which R.sub.3 represents a substituent chosen from a
heterocycloalkyl group and a hydroxyl group, a heterocycloalkyl
group comprising one or two heteroelements chosen from a nitrogen
atom and an oxygen atom, in particular a morpholinyl group, a
heteroaryl group optionally substituted with one or more
substituents chosen from a halogen atom, a (C.sub.1-C.sub.3)alkyl
group, a hydroxyl group and an --NH.sub.2 group; a heteroaryl
group, comprising one or more heteroatoms chosen from nitrogen
atoms, in particular a pyridyl group, and sulfur and oxygen atoms,
optionally substituted with one or more substituents chosen from: a
halogen atom, a (C.sub.1-C.sub.3)alkyl group optionally substituted
with one or more halogen atoms, a (C.sub.1-C.sub.5)alkoxy group,
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl
group optionally substituted with one or more substituents chosen
from a halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl
group and an --NH.sub.2 group, a group --NR.sub.5R.sub.5' in which
R.sub.5 and R.sub.5' independently, which may be identical or
different, represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, in particular a
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group, a heterocycloalkyl
group comprising one or more heteroatoms chosen from oxygen and
nitrogen atoms, said nitrogen atom being optionally substituted
with a substituent chosen from a formyl group and an acetyl group,
a group --NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6', which are
different, represent an alkyl group and a (C.sub.1-C.sub.5)alkoxy
group, R.sub.2 represents a hydrogen atom when n represents 1 and a
methyl group when n represents 0; in the form of the base or of an
addition salt with an acid or with a base.
Among the compounds of the present invention, mention may be made
of a seventh subgroup of compounds of formula (I) in which: Y
represents a bridged morpholine (a)
##STR00011## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached the substituent R.sub.1, R.sub.1
represents: a linear or branched (C.sub.1-C.sub.5)alkyl group, in
particular an isopropyl or tert-butyl group, a
(C.sub.3-C.sub.6)cycloalkyl group, an aryl group, in particular a
phenyl group, optionally substituted with one or more substituents
chosen from a halogen atom, a cyano group, an --NH.sub.2 group, a
urea group of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a
morpholinyl group, a group of formula
--SO.sub.2--(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)alkoxy
group, in particular a methoxy group, said alkoxy being optionally
substituted with one or more substituents chosen from: a halogen
atom, in particular a fluorine atom, a hydroxyl group or a
(C.sub.1-C.sub.5)alkoxy group, a group --COR.sub.3, in which
R.sub.3 represents a substituent chosen from a heterocycloalkyl
group and a hydroxyl group, a heterocycloalkyl group comprising one
or two heteroelements chosen from a nitrogen atom and an oxygen
atom, in particular a morpholinyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group; a heteroaryl group, comprising one or more
heteroatoms chosen from nitrogen atoms, in particular a pyridyl
group, and sulfur and oxygen atoms, optionally substituted with one
or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, an alkoxy group, optionally substituted with
one or more substituents chosen from a halogen atom, a
(C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and an
--NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5 and
R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, in particular a
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group, a heterocycloalkyl
group comprising one or more heteroatoms chosen from oxygen and
nitrogen atoms, said nitrogen atom being optionally substituted
with a substituent chosen from a formyl group, an acetyl group and
a --CO.sub.2--(C.sub.1-C.sub.5)alkyl group, a group
--NR.sub.6R.sub.6' in which R.sub.6 and R.sub.6', which are
different, represent an alkyl group and a (C.sub.1-C.sub.5)alkoxy
group, in the form of the base or of an addition salt with an acid
or with a base.
Among the compounds of the present invention, mention may be made
of an eighth subgroup of compounds of formula (I) in which: Y
represents a bridged morpholine (a)
##STR00012## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, R.sub.1
represents: a linear or branched (C.sub.1-C.sub.5)alkyl group, in
particular an isopropyl or tert-butyl group, a
(C.sub.3-C.sub.6)cycloalkyl group, an aryl group, in particular a
phenyl group, optionally substituted with one or more substituents
chosen from a halogen atom, a cyano group, an --NH.sub.2 group, a
urea group of formula --NH--CO--NH--(C.sub.1-C.sub.4)alkyl, a
morpholinyl group, a group of formula
--SO.sub.2--(C.sub.1-C.sub.5)alkyl, a (C.sub.1-C.sub.5)alkoxy
group, in particular a methoxy group, said alkoxy being optionally
substituted with one or more substituents chosen from: a halogen
atom, in particular a fluorine atom, a hydroxyl group or a
(C.sub.1-C.sub.5)alkoxy group, a group --COR.sub.3, in which
R.sub.3 represents a substituent chosen from a heterocycloalkyl
group and a hydroxyl group, a heterocycloalkyl group comprising one
or two heteroelements chosen from a nitrogen atom and an oxygen
atom, in particular a morpholinyl group, a heteroaryl group
optionally substituted with one or more substituents chosen from a
halogen atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and
an --NH.sub.2 group; a heteroaryl group, comprising one or more
heteroatoms chosen from nitrogen atoms, in particular a pyridyl
group, and sulfur and oxygen atoms, optionally substituted with one
or more substituents chosen from: a halogen atom, a
(C.sub.1-C.sub.3)alkyl group optionally substituted with one or
more halogen atoms, an alkoxy group, optionally substituted with
one or more substituents chosen from a halogen atom, a
(C.sub.3-C.sub.5)cycloalkyl group, a heteroaryl group optionally
substituted with one or more substituents chosen from a halogen
atom, a (C.sub.1-C.sub.3)alkyl group, a hydroxyl group and an
--NH.sub.2 group, a group --NR.sub.5R.sub.5' in which R.sub.5 and
R.sub.5', independently, which may be identical or different,
represent a substituent chosen from a hydrogen atom, a
--CO.sub.2--(C.sub.1-C.sub.3)alkyl group, a
(C.sub.3-C.sub.5)cycloalkyl group and a linear or branched
(C.sub.1-C.sub.3)alkyl group, said alkyl group being optionally
substituted with one or more hydroxyl groups, a pyridine group
bearing two linked adjacent groups forming, together with the two
carbons that bear them, a heterocycle comprising a nitrogen atom
and an oxygen atom, in particular a
3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine group, a heterocycloalkyl
group comprising one or more heteroatoms chosen from oxygen and
nitrogen atoms, in particular a morpholinyl group, a bridged
morpholinyl group and a piperidyl group, said nitrogen atom being
optionally substituted with a substituent chosen from a formyl
group and an acetyl group, a group --NR.sub.6R.sub.6' in which
R.sub.6 and R.sub.6', which are different, represent an alkyl group
and an alkoxy group, in the form of the base or of an addition salt
with an acid or with a base.
A ninth subgroup of compounds of formula (I) according to the
invention is such that: n represents 0 or 1; Y represents a bridged
morpholine chosen from (b) and (c)
##STR00013## L represents a linker --CH.sub.2--CO-- such that the
carbonyl function is attached to the substituent R.sub.1, or
(C.sub.1-C.sub.2)alkyl, said alkyl being optionally substituted
with a hydroxyl group; R.sub.1 represents: a linear or branched
(C.sub.1-C.sub.5)alkyl group, optionally substituted with an aryl
group, an aryl group, optionally substituted with one or more
substituents chosen from a halogen atom, a hydroxyl group and a
(C.sub.1-C.sub.5)alkoxy group, said alkoxy being optionally
substituted with one or more substituents chosen from: a group
--CONR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are as defined
below, a group --NR.sub.4R.sub.4' in which R.sub.4 and R.sub.4' are
as defined below, a heteroaryl group comprising one or more
heteroatoms chosen from a nitrogen atom, a sulfur atom and an
oxygen atom, optionally substituted with one or more
(C.sub.1-C.sub.3)alkyl groups, optionally substituted with one or
more halogen atoms, R.sub.2 represents a hydrogen atom when n
represents 1 and a methyl group when n represents 0; R.sub.4 and
R.sub.4', independently, which may be identical or different,
represent a hydrogen atom or a (C.sub.1-C.sub.3)alkyl group, in the
form of the base or of an addition salt with an acid or with a
base.
A tenth subgroup of compounds of formula (I) according to the
invention is such that L represents a linker --CH.sub.2--CO-- such
that the carbonyl function is attached to the substituent R.sub.1,
in the form of the base or of an addition salt with an acid or with
a base.
An eleventh subgroup of compounds of formula (I) according to the
invention is such that n represents 1, in the form of the base or
of an addition salt with an acid or with a base.
A twelfth subgroup of compounds of formula (I) according to the
invention is such that n represents 0, in the form of the base or
of an addition salt with an acid or with a base.
A thirteenth subgroup of compounds of formula (I) according to the
invention is such that R.sub.1 represents a heteroaryl group, in
particular a pyridyl group, in the form of the base or of an
addition salt with an acid or with a base.
A fourteenth subgroup of compounds of formula (I) according to the
invention is such that R.sub.1 represents a heterocycloalkyl group
comprising one or more heteroatoms chosen from oxygen and nitrogen
atoms, in particular a morpholinyl group, a bridged morpholinyl
group, a tetrahydropyranyl group and a piperidyl group, said
nitrogen atom being optionally substituted with a substituent
chosen from a formyl group, an acetyl group and a
--CO.sub.2--(C.sub.1-C.sub.4)alkyl group, in the form of the base
or of an addition salt with an acid or with a base.
The subgroups defined above, taken separately or in combination,
also form part of the invention. It should be noted that the
eleventh and twelfth subgroups cannot be combined together.
Among the compounds of formula (I) that are subjects of the
invention, mention may be made especially of the following
compounds: 1
(8S)-9-(2-Methyl-2-pyrid-4-ylpropyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e 2
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-y-
lethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
3
(8S)-9-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-oxa-5-azabicyclo[2.2.1]hept-
-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
4
(8S)-9-[2-(6-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 5
(8S)-9-[2-(6-Methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one 6
(8S)-9-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 7
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylet-
hyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
8
1-[2-(6-Dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(S)-methyl-7-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-
-a]pyrimidin-5-one 9
2-(S)-Methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a-
]pyrimidin-5-one 10
(8S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one 11
(S)-1-[2-(6-Aminopyrid-3-yl)-2-oxoethyl]-2-methyl-7-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a-
]pyrimidin-5-one 12
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
13
2-Methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-pyrid-3-ylethy-
l)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
14
(8S)-9-{2-[6-(2-Hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one 15
(8S)-9-[2-(5-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 16
2-Methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidaz-
o[1,2-a]pyrimidin-5-one 17
2-Methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidi-
n-5-one 18
2-Methyl-1-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidaz-
o[1,2-a]pyrimidin-5-one 19
(8S)-9-[2-(2-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 20
(8S)-9-[2-(4-Methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one 21
2-Methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3--
ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one 22
(8S)-9-[2-(6-Cyclopropylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one 23
1-Ethyl-3-{4-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-
-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phe-
nyl}urea 24
1-Ethyl-3-{4-[2-((S)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-y-
l-5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl)ethy-
l]phenyl}urea 25
(8S)-9-[2-(4-Methylthiazol-5-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one 26
2-Methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-azabic-
yclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]-
pyrimidin-5-one 27
(8S)-9-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one 28
1-[2-(3,5-Dimethyl-1H-pyrazol-4-yl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2--
a]pyrimidin-5-one 29
(8S)-9-(3,3-Dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
30
1-(3,3-Dimethyl-2-oxobutyl)-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one 31
(8S)-9-[2-(6-Amino-5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one 32
1-[2-(4-Aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-o-
ne 33
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(6-trif-
luoromethylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one 34
(8S)-9-(2-{6-[(2-Hydroxyethyl)methylamino]pyrid-3-yl}-2-oxoethyl)-2-(1S,4-
S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydro-
pyrimido[1,2-a]pyrimidin-4-one 35
(8S)-9-[2-(6-Ethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 36
(8S)-9-[2-(6-Amino-4,5-dimethylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S-
)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydrop-
yrimido[1,2-a]pyrimidin-4-one 37
(S)-9-[2-(4-Difluoromethoxyphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one 38
(8S)-9-[2-(3,4-Dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1-
S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahy-
dropyrimido[1,2-a]pyrimidin-4-one 39
(8S)-9-[2-(4-Methyloxazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one 40
(S)-9-[2-(3,4-Difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one 41
(8S)-9-[2-(4-Morpholin-4-ylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1-
,2-a]pyrimidin-4-one 42
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]benzonitrile
43
(8S)-9-[2-(4-Methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one 44
(8S)-9-[2-(5-Chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 45
(8S)-9-[2-(6-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-a-
zabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
-a]pyrimidin-4-one 46
(8S)-9-[2-(3-Methylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrim-
idin-4-one 47
(8S)-9-(2-Benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 48
(8S)-9-[2-(2,4-Difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 49
(8S)-9-(3-Ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 50
(8S)-9-(3-Hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 51
(8S)-9-(1-Methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 52
(8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one 53
(8S)-9-[2-(3,5-Dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 54
(8S)-9-(2-Ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
55
3-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]benzonitrile
56
(8S)-9-(3-Methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
57
{5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamic acid ethyl ester 58
{5-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamic acid methyl ester 59
(8S)-9-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrim-
idin-4-one 60
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(2-trifluoro-
methylpyrid-3-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one 61
(8S)-9-(2-Benzo[1,2,5]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 62
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydrop-
yran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one 63
(8S)-9-{2-[6-(2-Fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one 64
(8S)-9-{2-[3-Fluoro-4-(2-fluoroethoxyl)phenyl]-2-oxoethyl}-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one 65
(8S)-9-[2-(2-Methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one 66
(8S)-9-[2-(3-Methyl-3H-imidazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 67
(8S)-9-(2-Cyclopropyl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-
-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
68
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-y-
lethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
69
(8S)-9-[2-(2-Methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one 70 N,
N-Dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-5--
oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}ph-
enoxy)acetamide 71
(8S)-9-[(S)-2-(4-Fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabi-
cyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one 72
(2S)-1-[2-(4-Hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oc-
t-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
73
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-phenylethyl)-8-trif-
luoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 74
(2S)-1-{2-[4-(2-Dimethylaminoethoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-az-
abicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one 75
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 76
(S)-1-[2-(4-Methoxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-
-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
77
(S)-2-Methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-(3-phenylpropyl)-2-t-
rifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one 78
(S)-1-{2-[4-(3-Dimethylaminopropoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-az-
abicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one 79
(2S)-1-((S)-2-Hydroxy-2-phenylethyl)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1-
]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
80
(8S)-9-((S)-2-Hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-
-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
81
(8S)-9-[2-(4-Methoxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
82
(8S)-9-((R)-2-Benzo[b]thiophen-2-yl-2-hydroxyethyl)-2-(8-oxa-3-azabicyclo-
[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one 83
(8S)-9-[2-(4-Hydroxyphenyl)ethyl]-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
84
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluoro-
methylmethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 85
(8S)-2-(3-Oxa-8-azabicyclo[3.2.1]oct-8-yl)-9-(2-oxo-2-pyrid-3-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one 86
(8S)-9-(1-Difluoromethyl-1H-pyrazol-3-ylmethyl)-2-(8-oxa-3-azabicyclo[3.2-
.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin--
4-one 87
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-3-yle-
thyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
88
(8S)-2-(8-Oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-2-ylethyl)-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
89
(S)-9-[2-(1-Acetylpiperid-4-yl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-o-
ne 90
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifl-
uoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidin-
e-1-carbaldehyde 91
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]piperidine-1--
carboxylic acid ethyl ester 92
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4-
-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one 93
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyra-
n-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one 94
(8S)-9-(1-Acetylpiperid-4-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one 95
4-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorometh-
yl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carb-
aldehyde 96
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hy-
droxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one 97
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(4,4,4-trifluoro-3-hy-
droxy-3-trifluoromethylbutyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one 98
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(8-oxa-3-azabicycl-
o[3.2.1]oct-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one 99
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicycl-
o[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one 100
(8S)-9-[2-(1-Hydroxycyclopentyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one 101
(8S)-9-(1-Hydroxycyclopentylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 102
(8S)-9-(3,3-Dicyclopropyl-3-hydroxypropyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one 103
(8S)-9-(2,2-Dicyclopropyl-2-hydroxyethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one 104
(8S)-9-(1-Hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrim-
idin-4-one 105
(8S)-9-[2-(1-Hydroxycyclopropyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one 106
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylm-
ethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
107
(8S)-9-[2-(3-Methylisothiazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one 108
(8S)-9-[2-(4-Methanesulfonylphenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one 109
(8S)-9-Isoquinolin-5-ylmethyl-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-y-
l-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
110
(8S)-9-(2-Morpholin-4-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e 111
(8S)-9-{2-[4-(2-Morpholin-4-ylethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1-
,2-a]pyrimidin-4-one 112
N-Methoxy-N-methyl-2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6--
oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acet-
amide 113
(8S)-9-(2-Imidazo[1,2-a]pyrid-6-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1-
,2-a]pyrimidin-4-one 114
(8S)-9-[2-(6-Difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one 115
(S)-9-{2-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1-
,2-a]pyrimidin-4-one 116
(8S)-9-(1-Methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethyl)-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one 117
(8S)-9-{2-[4-(2-Dimethylaminoethoxyl)phenyl]ethyl}-2-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]-
pyrimidin-4-one 118
4-[2-((S)-8-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]piperidine-1--
carbaldehyde 119
(8S)-9-[2-(1-Acetylpiperid-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one in the form of the base or of an addition salt with an
acid or with a base.
It should be noted that the above compounds were named according to
the IUPAC nomenclature by means of the Autonom software.
In accordance with the invention, the compounds of general formula
(I) may be prepared according to the processes that follow.
The synthesis of the intermediate compounds E.sub.1 in which n=1
and R.sub.2 represents a hydrogen atom is described in Scheme
1:
##STR00014## The guanidine A is prepared according to the processes
described in patent application EP 1 460 076 by Lochead, A. W. et
al. Compound C may be obtained by condensation of a guanidine A
with a dialkyl malonate B, in which R is an alkyl group, preferably
an ethyl group, in the presence of a strong base such as sodium
methoxide, at a temperature of between 60.degree. C. and
100.degree. C., under the conditions described, for example, by
Badawey E.-S.A.M. et al. (Eur. J. Med. Chem., 1998, 33(5),
349-361). Compound D may be obtained from a compound C by treatment
with a chlorinating agent such as phosphorus oxychloride, in the
absence of solvent, at a temperature between 20.degree. C. and
120.degree. C., or in the presence of a polar solvent such as
1,2-dichloroethane, at a temperature of between 20.degree. C. and
the boiling point of the solvent, as described by Yamashita, A. et
al. (Syn. Commun. (2004), 34(5), 795-803). Compound E.sub.1 is
obtained after separation of the enantiomers of the compound of
formula D by chromatography on a chiral support.
The synthesis of the intermediate compounds E.sub.0 in which n=0
and R.sub.2 represents a methyl group is described in Scheme 2:
##STR00015## The diamine F is either commercially available or
prepared according to the process described in Journal of Organic
Chemistry (2006, 71(18), 7075-7078) by Brigaud, T. et al. The
guanidine G is obtained by reacting a diamine F and cyanogen
bromide in a polar solvent such as water or acetonitrile, at a
temperature of between 0.degree. C. and the boiling point of the
solvent, according to the conditions described in patent
application EP 1 340 761 by Gallet, T. et al. As previously, the
compounds H may be obtained by condensation of a guanidine G with a
dialkyl malonate B, in which R is an alkyl group, preferably an
ethyl group, in the presence of a strong base such as sodium
methoxide, at a temperature of between 60.degree. C. and
100.degree. C.
The compounds E.sub.0 are obtained from a compound H by treatment
with a chlorinating agent such as phosphorus oxychloride, in the
absence of solvent, at a temperature between 20.degree. C. and
120.degree. C., or in the presence of a polar solvent such as
1,2-dichloroethane, at a temperature of between 20.degree. C. and
the boiling point of the solvent. Thereafter, the products of
formula (I) as defined above according to the present invention may
thus be prepared according to Scheme 3.
##STR00016## The compounds I are obtained from a compound E, in
which n represents 0 or 1, and R.sub.2 represents a hydrogen atom
if n=1, or a methyl group if n=0, by reaction with a bridged
morpholine Y, in the absence of solvent, at a temperature of
between 20.degree. C. and 140.degree. C., or in the presence of a
polar solvent such as methyl isobutyl ketone or butyronitrile, at a
temperature of between 20.degree. C. and the reflux temperature of
the solvent. The compounds (I) may then be obtained via an
alkylation reaction, by addition of a compound J of formula
R.sub.1-L-Lg with R.sub.1 and L as defined above and Lg being a
leaving group such as Cl, Br, I or OTf (trifluoromethanesulfonate),
with compound I and a base such as sodium hydride, cesium carbonate
or potassium tert-butoxide in excess, in a polar solvent such as
acetonitrile, N,N-dimethylformamide or tetrahydrofuran, at a
temperature of between 0.degree. C. and 150.degree. C., as
described by Ting P. C. et al. (J. Med. Chem. (1990), 33(10),
2697-2706). By following the procedure described by E. P. Seest et
al. in Tet. Asymmetry 17 (2006) 2154-2182, the compounds J,
corresponding to chiral 1-aryl-2-chloroethanols or
1-heteroaryl-2-chloroethanols, were synthesized from the
corresponding chloro ketone derivatives, which were themselves
derived from chlorination of commercially available acetyl
derivatives under standard conditions. Alternatively, the compounds
(I) may be obtained from a compound K by reaction with a bridged
morpholine, in the absence of solvent, at a temperature of between
20.degree. C. and 140.degree. C., or in the presence of a solvent
such as methyl isobutyl ketone or butyronitrile, at a temperature
of between 20.degree. C. and the reflux temperature of the solvent.
The compounds K may be obtained via an alkylation reaction, by
addition of a compound J of formula R.sub.1-L-Lg with R.sub.1 and L
as defined above and Lg being a leaving group such as Cl, Br, I or
OTf, with compound E and a base such as sodium hydride, cesium
carbonate or potassium tert-butoxide in excess, in a solvent such
as acetonitrile, N,N-dimethylformamide or tetrahydrofuran, at a
temperature of between 0.degree. C. and 150.degree. C., as
described, for example, by Ting P. C. et al. (J. Med. Chem. (1990),
33(10), 2697-2706). The compounds of formula (I) for which the
linker L is an ethyl group, R.sub.1 is a linear or branched
(C.sub.1-C.sub.5)alkyl group substituted with a hydroxyl group, Y
represents a bridged morpholine chosen from (a), (b) and (c), n
represents 1 or 0, and R.sub.2 represents a hydrogen atom when n=1
and a methyl group when n=0, are noted (I)-1. The compounds for
which the linker L is a methyl group, R.sub.1 is a linear or
branched (C.sub.1-C.sub.5)alkyl group substituted with a hydroxyl
group, Y represents a bridged morpholine chosen from (a), (b) and
(c), n represents 1 or 0, and R.sub.2 represents a hydrogen atom
when n=1 and a methyl group when n=0, are noted (I)-2. The
compounds of formula (I) for which the linker L is a methyl group,
R.sub.1 is a group --NR.sub.6R.sub.6' with R.sub.6 et R.sub.6'
being either different and representing an alkyl group and an
alkoxy group, or R.sub.6 and R.sub.6' together forming a monocyclic
or bicyclic heterocycloalkyl, Y represents a bridged morpholine
chosen from (a), (b) and (c), n represents 1 or 0, and R.sub.2
represents a hydrogen atom when n=1 and a methyl group when n=0,
are noted (I)-3. The compounds of formulae (I)-1, (I)-2 and (l)-3
may be obtained according to Scheme 4.
##STR00017## The compounds (1)-1 may be obtained via an alkylation
reaction, by addition to a compound N of a compound O, of formula
Z--Mg--X in which Z represents a linear or branched alkyl radical
and X is a halogen atom such as Cl or Br, in a polar solvent such
as tetrahydrofuran, at a temperature of between 0.degree. C. and
25.degree. C., as described, for example, by Ting P. C. et al. (J.
Med. Chem. (1990), 33(10), 2697-2706). The compounds N may be
obtained via an addition reaction of Michael type of a compound E
with a compound M, of formula CH.sub.2.dbd.CH.sub.2--CO.sub.2Alkyl,
in the presence of a base such as
1,8-diazabicyclo[5.4.0]undec-7-ene, in a polar aprotic solvent such
as N,N-dimethylformamide, at a temperature of 25.degree. C.
Similarly, the compounds (l)-2 may be obtained via an alkylation
reaction, by addition of a compound O, as described above, to
compound Q, in a polar solvent such as tetrahydrofuran, at a
temperature of between 0.degree. C. and 25.degree. C. The compounds
Q may be obtained via an alkylation reaction, by addition of a
compound P, of formula X--CH.sub.2--CO.sub.2Alkyl in which X is a
halogen atom such as Cl, Br or I, to compound E and an alkaline
base such as sodium hydride or cesium carbonate in excess, in a
polar solvent such as N,N-dimethylformamide or acetonitrile, at a
temperature of 25.degree. C. The compounds (I)-3 may be obtained
via a coupling reaction between a compound S and a compound of
formula HNR.sub.6R.sub.6' with R.sub.6 and R.sub.6' being either
different and representing an alkyl group and an alkoxy group, or
R.sub.6 and R.sub.6' together forming a monocyclic or bicyclic
heterocycloalkyl, in a polar solvent such as N,N-dimethylformamide,
in the presence of coupling agents such as 1-hydroxy benzotriazole
with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
Compound S is obtained by hydrolysis of compound Q, for example
using lithium hydroxide monohydrate in a water/tetrahydrofuran
mixture. It is clear to a person skilled in the art that, in order
to perform the processes according to the invention described
previously, it may be necessary to introduce protecting groups for
the amino, carboxyl and alcohol functions in order to avoid side
reactions.
Examples of protecting groups and also of protection and
deprotection methods are given in Protective Groups in Organic
Synthesis, Greene et al., 3rd Edition (John Wiley & Sons, Inc.,
New York). As examples of protection of reactive functions, the
following non-exhaustive list may be mentioned:
the hydroxyl groups may be protected, for example, with alkyl
radicals such as tert-butyl, trimethylsilyl,
tert-butyldimethylsilyl, methoxymethyl, tetrahydropyranyl, benzyl
or acetyl,
the amino groups may be protected, for example, with acetyl,
trityl, benzyl, tert-butoxycarbonyl, benzyloxycarbonyl or
phthalimido radicals or other radicals known in peptide
chemistry,
the acid functions may be protected, for example, in the form of
esters formed with readily cleavable esters such as benzyl or
tert-butyl esters or esters known in peptide chemistry.
In the text hereinabove, the term "leaving group Lg" means a group
that can be readily cleaved from a molecule by breaking a
heterolytic bond, with loss of an electron pair. This group can
thus be easily replaced with another group in a substitution
reaction, for example. Such leaving groups are, for example,
halogens or an activated hydroxyl group, such as a mesylate,
tosylate, triflate, acetyl, etc. Examples of leaving groups and
also references for preparing them are given in Advanced Organic
Chemistry, J. March, 4th Edition, Wiley Interscience, p.
310-316.
In schemes 1, 2, 3 and 4, the starting compounds and the reagents,
when the method for preparing them is not described, are
commercially available or described in the literature, or else can
be prepared according to methods which are described therein or
which are known to those skilled in the art.
According to another of its aspects, a subject of the invention is
also the compounds of formulae I, N, Q and S. These compounds are
useful as intermediates in the synthesis of the compounds of
formula (I).
The following abbreviations and molecular formulae are used:
EtOAc: ethyl acetate
Br: bromine
CDCl.sub.3: deuterated chloroform
Cl: chlorine
DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM: dichloromethane
DMF: N,N-dimethylformamide
DMSO: dimethyl sulfoxide
DMSO-d.sub.6: deuterated dimethyl sulfoxide
HPLC: high performance liquid chromatography
HCl: hydrochloric acid
K.sub.2CO.sub.3: potassium carbonate
LC/MS: liquid chromatography/mass spectrometry
MeOH: methanol
MgSO.sub.4: magnesium sulfate
MHz: Megahertz
Na.sub.2CO.sub.3: sodium carbonate
NaCl: sodium chloride
NaOH: sodium hydroxide
NaHCO.sub.3: sodium hydrogen carbonate
Na.sub.2SO.sub.4: sodium sulfate
Ph: phenyl
Pd/C: palladium-on-charcoal
Pd(OH).sub.2/C: palladium hydroxide-on-charcoal
TFA: trifluoroacetic acid
THF: tetrahydrofuran
.degree. C.: degrees Celsius
Tr: retention time
min: minutes
ESI+: positive-mode electrospray ionization
The following examples describe the preparation of certain
compounds in accordance with the invention. These examples are not
limiting and merely illustrate the present invention. The numbers
of the compounds exemplified refer to those given in the table
hereinafter, which shows the chemical structures and the physical
properties of some compounds according to the invention.
It should be noted that the compounds described in the experimental
section were named according to the IUPAC nomenclature by means of
the Autonom software.
In the procedures and examples below:
the microwave oven used is a Biotage, Initiator.TM. Eight, 400 W
max, 2450 MHz apparatus. the proton magnetic resonance spectra
(.sup.1H NMR), as described below, are recorded at a temperature of
300 K (exchangeable protons not recorded) at 300, 400 or 600 MHz in
DMSO-d.sub.6 or CDCl.sub.3, using the DMSO-d.sub.6 or CDCl.sub.3
peak as reference. The chemical shifts 6 are expressed in parts per
million (ppm). The signals observed are expressed as follows:
s=singlet, d=doublet, m=multiplet, bs=broad signal, t=triplet,
q=quartet. the LC/MS characteristics, as described below (A, B, C,
D, E, F and G) indicate, successively, the analytical method used
and detailed below, the retention time (Tr) of the compound
expressed in minutes and the peak [M+H]+ identified by mass
spectrometry.
Method A
Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer
(Waters)
Column: Ascentis Express C18 50.times.2.1 mm 2.7 .mu.m,
T.degree.=55.degree. C.
Solvent A: H.sub.2O+0.02% TFA; Solvent B: acetonitrile+0.014%
TFA
Flow rate: 1 mL/min
Gradient A/B: t 0 min 2% B, t 1 min 98% B, t 1.3 min 98% B, t 1.33
min 2% B
Detection: UV 220 nm
Ionization: electrospray positive mode
Method B
Instrument: Acquity UPLC chain (Waters); LCT mass spectrometer
(Waters)
Column: BHE C8 50.times.2.1 mm 1.7 .mu.m, T.degree.=55.degree.
C.
Solvent A: H.sub.2O+0.02% TFA; Solvent B: acetonitrile+0.014%
TFA
Flow rate: 1 mL/min
Gradient A/B: t 0 min 2% B, t 1 min 98% B, t 1.3 min 98% B, t 1.33
min 2% B
Detection: UV 220 nm
Ionization: electrospray positive mode
Method C
Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer
(Waters)
Column: BHE C18 50.times.2.1 mm 1.7 .mu.m, T.degree.=50.degree.
C.
Solvent A: H.sub.2O+0.02% HCO.sub.2H; Solvent B: acetonitrile+0.02%
HCO.sub.2H
Flow rate: 1 mL/min
Gradient A/B: t 0 min 5% B, t 2 min 100% B, t 2.5 min 100% B
Detection: UV 220 nm
Ionization: electrospray positive mode
Method D
Instrument: Acquity UPLC chain (Waters); SQD mass spectrometer
(Waters)
Column: Acquity BHE C18 50.times.2.1 mm 1.7 .mu.m,
T.degree.=50.degree. C.
Solvent A: H.sub.2O+0.1% HCO.sub.2H; Solvent B: acetonitrile+0.1%
HCO.sub.2H
Flow rate: 1 mL/min
Gradient A/B: t 0 min 5% B, t 0.8 min 50% B, t 1.2 min 100% B, t
1.85 min 100% B, t 1.95 min 5% B
Detection: UV 220 nm Ionization: electrospray positive mode
Method E
Instrument: HPLC chain (Waters); ZQ mass spectrometer (Waters)
Column: XBridge C18 50.times.3 mm 2.5 .mu.m, T.degree.=70.degree.
C.
Solvent A: H.sub.2O+0.1% HCO.sub.2H; Solvent B: acetonitrile+0.1%
HCO.sub.2H
Flow rate: 0.9 mL/min
Gradient A/B: t 0 min 5% B, t 5.3 min 100% B, t 5.5 min 100% B, t
6.3 min 5% B
Detection: UV 220 nm
Ionization: electrospray positive mode
Method F
Instrument: Acquity UPLC type HPLC chain (Waters); SQD mass
spectrometer (Waters)
Column: BHE C18 30.times.2.1 mm 1.7 .mu.m, T.degree.=50.degree.
C.
Solvent A: H.sub.2O+0.1% HCO.sub.2H; Solvent B: acetonitrile+0.1%
HCO.sub.2H
Flow rate: 1 mL/min
Gradient A/B: t 0 min 5% B, t 2 min 100% B, t 2.5 min 100% B
Detection: UV 220 nm
Ionization: electrospray positive mode
Method G
Instrument: Alliance HPLC chain (Waters); ZQ mass spectrometer
(Waters)
Column: X Bridge C18 30.times.2.1 mm 2.5 .mu.m,
T.degree.=55.degree. C.
Solvent A: H.sub.2O+0.02% TFA; Solvent B: MeOH
Flow rate: 0.7 mL/min
Gradient A/B: t 0 min 2% B, t 3 min 100% B, t 3.5 min 100% B, t 3.6
min 2% B
Detection: UV 220 nm
Ionization: electrospray positive mode
The optical rotations [.alpha.].sub.D.sup.25 were measured on a
model 341 polarimeter from Perkin-Elmer. Wavelength: sodium .alpha.
line (589 nm).
EXAMPLE 1
(8S)-9-[2-(2,4-difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one (Compound 48)
##STR00018##
Step 1.1:
4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine
##STR00019##
A mixture of 6 g of 10% Pd/C and 60 g (370 mmol) of
2-amino-4-(trifluoromethyl)pyrimidine dissolved in 80 mL of water,
250 mL of isopropanol and 24 mL (370 mmol) of methanesulfonic acid
is hydrogenated at 5 bar, at 40.degree. C., for 5 hours in an
autoclave. The resulting mixture is then filtered and rinsed with
isopropanol and with water. The filtrate is then concentrated under
reduced pressure and the residue obtained is dried under vacuum to
give 93.5 g of
4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine
methanesulfonate in the form of a white solid. The white solid is
dissolved in 250 mL of methyl isobutyl ketone. 100 mL of 10 N
sodium hydroxide are then added. The mixture is stirred at room
temperature for 15 minutes. The phases are separated by settling
and the aqueous phase is re-extracted with methyl isobutyl ketone.
The organic phases are combined and then evaporated under vacuum.
59.50 g of 4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine
are thus obtained, the characteristics of which are as follows:
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.46 (m, 1H),
1.84 (m, 1H), 3.15 (m, 2H), 3.80 (m, 1H), 4.51-5.20 (bs, 2H),
5.55-6.30 (bs, 1H).
Step 1.2:
2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one
##STR00020## 62.10 g (1150 mmol) of sodium methoxide are added to a
mixture of 340 mL (2230 mmol) of diethyl malonate heated to
40.degree. C. The mixture is heated at 100.degree. C. until a clear
solution is obtained. 59.50 g (360 mmol) of
4-trifluoromethyl-1,4,5,6-tetrahydropyrimidin-2-ylamine dissolved
in 100 mL of methanol are then added to the reaction medium. The
mixture obtained is maintained at 100.degree. C. for 1 hour and
then cooled to room temperature overnight. The reaction mixture is
evaporated to dryness under reduced pressure. The residue obtained
is taken up in 250 mL of water. 12 N hydrochloric acid is added to
the thick suspension obtained, to pH=5-6. The suspension obtained
is filtered through a sinter funnel and the insoluble matter is
rinsed with acetonitrile to give 68.10 g of
2-hydroxy-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one in the form of a yellow solid, the characteristics of which are
as follows:
LC/MS (method D), ESI+: [M+H]+: m/z 236; tr (min)=0.26
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.46 (m, 1H),
1.84 (m, 1H), 3.15 (m, 2H), 3.80 (m, 1H), 4.51-5.20 (bs, 2H),
5.55-6.30 (bs, 1H).
Step 1.3:
2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one
##STR00021## 136 mL (1440 mmol) of phosphorus oxychloride are
added, at room temperature and under an argon atmosphere, to a
suspension of 68.10 g (290 mmol) of
2-hydroxy-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimi-
din-4-one in 950 mL of 1,2-dichloroethane. The mixture obtained is
then heated at 65.degree. C. for 3 hours. After cooling, the
reaction mixture is evaporated to dryness under reduced pressure.
The residue obtained is taken up in 140 mL of cold water and 430 mL
of ethyl acetate. 32% sodium hydroxide is added to the mixture
obtained, to pH=5. The resulting organic phase is separated out and
then dried over magnesium sulfate, filtered and concentrated under
reduced pressure to give 60 g of
2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimid-
in-4-one in the form of an orange solid, the characteristics of
which are as follows:
LC/MS (method D), ESI+: [M+H]+: m/z 254; tr (min)=0.51
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6) 2.16 (m, 2H)
3.45 (m, 1H) 4.12 (m, 1H) 4.42 (m, 1H) 5.83 (s, 1H) 9.12 (s,
1H)
Step 1.4:
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one
##STR00022## The separation of the two enantiomers of
2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-
-4-one (100 g) is performed by chiral chromatography: stationary
phase: Chiralpak IA (250 mm.times.4.6) 5 .mu.m; temperature
25.degree. C.; mobile phase: methanol (100%). The levorotatory
enantiomer is concentrated to give 49.10 g of
(8R)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]py-
rimidin-4-one, in the form of a white powder. The dextrorotatory
enantiomer is concentrated to obtain 48.5 g of
(8S)-2-chloro-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]py-
rimidin-4-one, in the form of a white powder, the characteristics
of which are as follows:
LC/MS (method D), ESI+: [M+H]+: m/z 254; tr (min)=0.51
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.14 (m, 2H),
3.47 (m, 1H), 4.12 (m, 1H), 4.36 (m, 1H), 5.81 (s, 1H), 9.31 (s,
1H).
[.alpha.].sub.D.sup.25 at 589 nm=+21.3.+-.0.5.degree. (MeOH)
Step 1.5:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00023##
1.60 g (6.31 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 1.30 g (9.46 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 2.21 mL
(15.77 mmol) of triethylamine are added. The tube is sealed and
heated at 130.degree. C. in an oil bath for 6 hours. After cooling,
the crude product is purified by chromatography on silica gel
(eluent: 95/5 EtOAc/MeOH). After evaporating the fractions under
reduced pressure, 1.20 g of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluorome-
thyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained,
the characteristics of which are as follows:
LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min)=1.37
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2 (m, 2H), 2.35
(m, 2H), 3.45 (m, 2H), 3.92 (s, 1H), 3.95-4.32 (m, 4H), 4.78 (s,
1H), 4.89-5.2 (bs, 1H), 5.49-5.77 (bs, 1H).
Step 1.6:
(8S)-9-[2-(2,4-difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one
##STR00024##
A suspension of 150 mg (0.47 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 463.57 mg (1.42
mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for
15 minutes at room temperature. 222.93 mg (0.95 mmol) of
2-bromo-1-(2,4-difluorophenyl)ethanone are then added. After
stirring overnight at room temperature, the reaction mixture is
evaporated and the residue is taken up in water and extracted with
ethyl acetate. The organic phase is dried over magnesium sulfate
and then evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 130
mg of
(8S)-9-[2-(2,4-difluorophenyl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 471 tr (min)=0.68
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.58-1.76 (m,
2H), 2.13-2.29 (m, 1H), 2.39-2.47 (m, 1H), 2.95-3.13 (bs, 4H),
3.16-3.29 (m, 1H), 4.34 (m, 1H), 4.41 (s, 1H), 4.51 (s, 1H),
4.58-4.71 (m, 3H), 5.38 (m, 1H), 7.3 (m, 1H), 7.51 (m, 1H), 8 (q,
1H)
EXAMPLE 2
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one (Compound 25)
##STR00025##
Step 2.1: 5-(2-bromoethyl)-4-methylthiazole
##STR00026##
A solution of 1 g (7 mmol) of 4-methyl-5-thiazolylethanol in 15 mL
of dichloromethane is cooled to 0.degree. C. under argon. In a
first stage, 1.8 g (7 mmol) of triphenylphosphine are added. Next,
1.30 g (7 mmol) of N-bromosuccinimide are added portionwise over 5
minutes. After stirring for 2 hours at 0.degree. C., the solvent is
evaporated off under vacuum. The residue obtained is purified by
chromatography on silica gel (eluent: 50/50 EtOAc/heptane) to give
900 mg of 5-(2-bromoethyl)-4-methylthiazole, the characteristics of
which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 207 tr (min)=1.52
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.42 (s, 3H),
3.3-3.35 (t, 2H), 3.5-3.55 (t, 2H), 8.62 (s, 1H).
Step 2.2:
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-a-
zabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
-a]pyrimidin-4-one
##STR00027##
A suspension of 160 mg (0.50 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 415 mg (1.25 mmol)
of cesium carbonate in 4 mL of N,N-dimethylformamide is heated at
80.degree. C. for 15 minutes. After cooling to room temperature, a
solution of 150 mg (0.76 mmol) of 5-(2-bromoethyl)-4-methylthiazole
in 1 mL of N,N-dimethylformamide is added dropwise. The reaction
medium is heated at 80.degree. C. overnight. The reaction mixture
obtained is evaporated to dryness. The residue obtained is taken up
in water and extracted with ethyl acetate. The organic phase is
dried over magnesium sulfate and evaporated to dryness.
The residue is purified by chromatography on silica gel (eluent:
95/5 EtOAc/MeOH) to give 40 mg of
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 442 tr (min)=0.55
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.85 (t, 2H),
2.13 (m, 1H), 2.32 (s, 3H), 2.36 (m, 1H), 3.05-3.32 (m, 4H), 3.36
(d, 1H), 3.45 (m, 1H), 3.67 (d, 1H), 3.75 (d, 1H), 4.15-4.22 (m,
2H), 4.57 (m, 1H), 4.63 (s, 1H), 4.71 (s, 1H), 4.8 (s, 1H), 8.8 (s,
1H).
EXAMPLE 3
(8S)-9-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one (Compound 15)
##STR00028##
Step 3.1: 1-(5-methylpyrid-3-yl)ethanone
##STR00029##
The following are successively introduced into a microwave
tube:
484 .mu.l (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of
H.sub.2O/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of
tributyl(1-ethoxyvinyl)tin, 57.12 mg (0.081 mmol) of
bis(triphenylphosphine)palladium(II) chloride, 1.12 g (8.14 mmol)
of potassium carbonate. This mixture is subjected to microwave
irradiation at 110.degree. C. for 1 hour. The reaction mixture is
evaporated to dryness and the residue is then taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness. The residue obtained
is taken up in 6 mL of methanol and 1 mL of 6 N HCl, and the
solution is stirred overnight at room temperature. The reaction
medium is evaporated to dryness and the residue is taken up in
saturated aqueous NaHCO.sub.3 solution and extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate and
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 50/50 EtOAc/heptane) to give 300 mg of
1-(5-methylpyrid-3-yl)ethanone, the characteristics of which are as
follows:
LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min)=0.78
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.37 (s, 3H),
2.62 (s, 3H), 8.1 (s, 1H), 8.63 (s, 1H), 8.93 (s, 1H).
Step 3.2: 2-bromo-1-(5-methylpyrid-3-yl)ethanone hydrobromide
##STR00030##
300 mg (2.22 mmol) of 1-(5-methylpyrid-3-yl)ethanone are dissolved
in 15 mL of glacial acetic acid. 365 .mu.l (2.22 mmol) of
hydrobromic acid and 126 .mu.l (2.44 mmol) of bromine are added to
the medium. The reaction mixture is placed under magnetic stirring
at room temperature for 2 hours. Ethyl ether is added to the
solution until a precipitate appears. The precipitate corresponding
to 2-bromo-1-(5-methylpyrid-3-yl)ethanone hydrobromide is filtered
off, washed with ether and dried. The 600 mg of product obtained
have the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min)=1.17
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.46 (s, 3H),
5.05 (s, 2H), 8.48 (s, 1H), 8.82 (s, 1H), 9.12 (s, 1H).
Step 3.3: (8S)-9-[2-(5-methyl
pyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-tr-
ifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00031##
150 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are
added to a suspension of 50.08 mg (1.04 mmol) of sodium hydride in
5 mL of DMF. The reaction mixture is placed under magnetic stirring
at room temperature for 15 minutes. A solution of 153.88 mg (0.522
mmol) of 3-(bromoacetyl)pyridine hydrobromide in 5 mL of DMF is
added dropwise to the reaction medium. The reaction is stirred at
room temperature overnight. The reaction medium is evaporated to
dryness. The crude product is taken up in water and extracted with
ethyl acetate. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 70
mg of
(8S)-9-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.51
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62-1.7 (dd,
2H), 2.25 (m, 1H), 2.4 (s, 3H), 2.43 (m, 1H), 2.96-3.2 (m, 3H),
3.2-3.33 (m, 2H), 4.37 (m, 1H), 4.42 (s, 1H), 4.47 (s, 1H), 4.57
(m, 1H), 4.63-4.7 (m, 2H), 5.6 (d, 1H), 8.16 (s, 1H), 8.67 (s, 1H),
8.98 (s, 1H).
EXAMPLE 4
(8S)-9-[2-(3,5-di
methylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 53)
##STR00032##
Step 4.1:
N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide
##STR00033##
659 .mu.l (8.15 mmol) of pyridine are added to a suspension of
343.07 mg (3.45 mmol) of N,O-dimethylhydroxylamine hydrochloride in
10 mL of dichloromethane. The mixture is stirred at room
temperature until fully dissolved. A solution of 526.32 mg (3.13
mmol) of 3,5-dimethylisoxazole-4-carbonyl chloride in 5 mL of
dichloromethane is then added. After stirring for 1 hour at room
temperature, the reaction mixture is taken up in saturated aqueous
NaHCO.sub.3 solution and stirred for a few minutes, and the phases
are separated by settling. The organic phase is dried over
magnesium sulfate and evaporated to dryness. The residue obtained
is taken up in toluene and evaporated, the operation being repeated
a second time. 570 mg of
N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide are then
obtained, corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 185 tr (min)=1.08
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.32 (s, 3H),
2.46 (s, 3H), 3.34 (s, 3H), 3.52 (s, 3H).
Step 4.2: 1-(3,5-dimethylisoxazol-4-yl)ethanone
##STR00034##
A solution of 580 mg (3.15 mmol) of
N-methoxy-N-methyl-3,5-dimethylisoxazole-4-carboxamide in 20 mL of
THF is cooled to 0.degree. C. A solution of 1.57 mL (4.72 mmol) of
3 M methylmagnesium bromide in ether is added. After stirring for 4
hours at room temperature, the reaction medium is taken up in 10 mL
of 1 N HCl and stirred for a further 1 hour at room temperature.
The mixture is then basified with K.sub.2CO.sub.3 and extracted
with ethyl acetate. The organic phase is dried over magnesium
sulfate and evaporated to dryness to give 420 mg of
1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the
following characteristics:
LC/MS (method G): [M+H]+: m/z 140 tr (min)=1.06
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, CDCl.sub.3): 2.48
(s, 6H), 2.70 (s, 3H).
Step 4.3: 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone
##STR00035##
400 mg (2.87 mmol) of 1-(3,5-dimethylisoxazol-4-yl)ethanone are
dissolved in 20 mL of glacial acetic acid. 1.42 mL (8.62 mmol) of
hydrobromic acid and 163 .mu.l (3.16 mmol) of bromine are added to
the medium. The reaction mixture is placed under magnetic stirring
at room temperature for 2 hours. The solution is diluted with
water, basified with saturated aqueous NaHCO.sub.3 solution and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness to give 540 mg of
2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 218 tr (min)=1.35
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.52 (s, 3H),
2.74 (s, 3H), 4.18 (s, 2H).
Step 4.4:
(8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-tri-
fluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00036##
A suspension of 150 mg (0.591 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 154.76
mg (0.709 mmol) of 2-bromo-1-(3,5-dimethylisoxazol-4-yl)ethanone
are then added. After stirring overnight at room temperature, the
reaction mixture is evaporated and the residue is taken up in water
and extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness to give 230 mg of
(8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding
to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 391 tr (min)=2.06
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.44 (s, 2H),
2.7 (s, 3H), 3.46 (m, 1H), 4 (m, 2H), 4.54 (m, 1H), 5.23 (s, 3H),
5.53 (d, 1H), 5.92 (s, 1H).
Step 4.5:
(8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one
##STR00037##
200 mg (0.51 mmol) of
(8S)-2-chloro-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 83.28 mg
(0.61 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
hydrochloride are mixed together. The powder obtained is placed in
a tube and 178 .mu.l (1.28 mmol) of triethylamine are added. The
tube is sealed and heated at 130.degree. C. in an oil bath for 6
hours. The crude product obtained is taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and then evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH)
to give 130 mg of
(8S)-9-[2-(3,5-dimethylisoxazol-4-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 454 tr (min)=0.58
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.44 (s, 2H),
2.7 (s, 3H), 3.46 (m, 1H), 4 (m, 2H), 4.54 (m, 1H), 5.23 (s, 3H),
5.53 (d, 1H), 5.92 (s, 1H).
EXAMPLE 5
(8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl--
8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 56)
##STR00038##
Step 5.1: 1-bromo-3-methylbutan-2-one
##STR00039##
A solution of 1 g (11.61 mmol) of 3-methylbutan-2-one in 6 mL of
methanol is cooled to a temperature of 10.degree. C. When the
temperature is reached, 597 .mu.l (11.61 mmol) of bromine are
added. The reaction mixture is stirred at 10.degree. C. until fully
decolorized, and stirring is then continued for 30 minutes at room
temperature. After adding 10 mL of water to the solution, stirring
is continued for 1 hour at room temperature. The reaction mixture
is then taken up in water and extracted with ethyl ether. The
organic phase is washed with aqueous 10% Na.sub.2CO.sub.3 solution
and then with saturated NaCl solution, dried and evaporated to give
1.50 g of 1-bromo-3-methylbutan-2-one, corresponding to the
following characteristics:
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.15 (s, 3H),
1.18 (s, 3H), 2.92-3.06 (m, 1H), 4 (s, 2H).
Step 5.2:
(8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9--
tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00040##
A suspension of 170 mg (0.670 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 655.21 mg (2.01 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 132.75
mg (0.804 mmol) of 1-bromo-3-methylbutan-2-one are then added.
After stirring overnight at room temperature, the reaction mixture
is evaporated and the residue is taken up in water and extracted
with ethyl acetate. The organic phase is dried over magnesium
sulfate and evaporated to dryness to give 220 mg of
(8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydr-
opyrimido[1,2-a]pyrimidin-4-one, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 338 tr (min)=2.20
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.13 (m, 6H),
2.38 (m, 2H), 2.68 (m, 1H), 3.41 (m, 1H), 3.87 (m, 2H), 4.51 (m,
1H), 5.2 (d, 1H), 5.9 (s, 1H).
Step 5.3:
(8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]-
hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-o-
ne
##STR00041##
220 mg (0.51 mmol) of
(8S)-2-chloro-9-(3-methyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetrahydr-
opyrimido[1,2-a]pyrimidin-4-one and 105.99 mg (0.78 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 227 .mu.l
(1.63 mmol) of triethylamine are added. The tube is sealed and
heated at 130.degree. C. in an oil bath for 3 hours. The crude
product obtained is taken up in ethyl acetate and the organic phase
is washed with water, dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 EtOAc/MeOH) to give 100 mg of
(8S)-9-(3-methyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 401 tr (min)=0.6
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.02 (m, 6H),
1.79 (m, 2H), 2.16 (m, 1H), 2.37 (m, 1H), 2.68 (m, 1H), 2.84-3.26
(bs, 3H), 3.30-3.75 (bs, 2H), 4.18 (d, 1H), 4.30 (m, 1H), 4.46 (m,
1H), 4.60 (s, 1H), 4.63-4.96 (bs, 2H), 5 (m, 1H).
EXAMPLE 6
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-yleth-
yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 7)
##STR00042##
Step 6.1:
(8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,-
8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00043##
A suspension of 750 mg (15.77 mmol) of sodium hydride in 50 mL of
DMF is cooled to 0.degree. C. under argon. A solution of 2 g (7.89
mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one in 50 mL of DMF is added dropwise. The mixture is stirred
for 10 minutes at room temperature. After cooling the reaction
medium to 0.degree. C., 2.92 g (9.86 mmol) of
3-(bromoacetyl)pyridine hydrobromide are added portionwise. The
reaction mixture is allowed to warm to room temperature and is
stirred overnight. The reaction medium is evaporated to dryness and
the residue is taken up in water and extracted with EtOAc. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. The crude product obtained is purified by chromatography
on silica gel (eluent: 100% EtOAc). After evaporating the fractions
under reduced pressure, 1.90 g of
(8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one are obtained, the
characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 373 tr (min)=1.76
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.66 (s, 1H),
2.3-2.52 (m, 2H), 3.48 (m, 1H), 4 (m, 1H), 4.37 (d, 1H), 4.56 (m,
1H), 5.92 (s, 1H), 7.45 (m, 1H), 8.22 (m, 1H), 8.81 (s, 1H), 9.15
(s, 1H).
Step 6.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyr-
id-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one
##STR00044##
1 g (2.68 mmol) of
(8S)-2-chloro-9-(2-oxo-2-pyrid-3-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one and 545.67 mg (4.02 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 934.86 .mu.l
(6.71 mmol) of triethylamine are added. The tube is sealed and
heated at 130.degree. C. in an oil bath for 6 hours. The crude
product obtained is taken up in water and extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 EtOAc/MeOH) to give 980 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-3-ylet-
hyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min)=0.51
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.67 (d, 1H),
1.75 (d, 1H), 2.32 (m, 1H), 2.5 (m, 1H), 3.04 (d, 1H), 3.17-3.25
(bs, 1H), 3.25-3.4 (bs, 3H), 4.44 (dd, 1H), 4.48 (s, 1H), 4.52 (s,
1H), 4.66 (m, 1H), 4.72 (s, 1H), 4.77 (d, 1H), 5.7 (d, 1H), 7.64
(m, 1H), 8.41 (m, 1H) 8.88 (m, 1H), 9.24 (s, 1H).
EXAMPLE 7
2-methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one (Compound 16)
##STR00045##
Step 7.1: (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine
##STR00046##
25 g (180 mmol) of (R)-phenylglycinol and then 4 g (16 mmol) of
pyridinium para-toluenesulfonate are added to a solution of 25.8 g
(230 mmol) of trifluoroacetone in 200 mL of toluene in a
three-necked flask on which is mounted Dean-Stark apparatus. The
mixture obtained is then heated at 110.degree. C. for 5 hours.
After cooling, the reaction mixture is concentrated under reduced
pressure. The residue obtained is purified by filtration on silica
(eluent: dichloromethane) to give 35.10 g of
(R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine in the form of a
colorless liquid, the characteristics of which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 232 tr (min)=0.96
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.55 (s, 3H),
3.58 (m, 1H), 3.80 (m, 1H), 4.28 (m, 1H), 4.42 (m, 1H), 7.34 (m,
5H).
[.alpha.].sub.D.sup.25 at 589 nm=-23.4.+-.0.8.degree. (c=1.794
mg/0.5 mL MeOH)
Step 7.2:
(S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methy-
lpropionitrile
##STR00047## 25 mL (200 mmol) of trimethylsilyl cyanide are added
dropwise to a solution, cooled to 2.degree. C., of 30.10 g (130
mmol) of (R)-2-methyl-4-phenyl-2-trifluoromethyloxazolidine in 300
mL of dichloromethane in a three-necked flask under argon, followed
by dropwise addition of 25 mL (200 mmol) of boron trifluoride
etherate. The cold bath is then removed to allow the mixture to
warm to room temperature. The resulting mixture is stirred at room
temperature for 3 hours, followed by addition of saturated sodium
bicarbonate solution to pH=7. The organic phase is separated out
and then dried over magnesium sulfate, filtered and concentrated
under reduced pressure. The residue obtained is purified by
chromatography on silica (eluent A/B: pentane/EtOAc, A/B gradient:
t 0 min 0% B, t 20 min 10% B, t 40 min 40% B) to give 3.50 g of
(R)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropioni-
trile in the form of a colorless oil and 10 g of
(S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropioni-
trile in the form of a white solid, the characteristics of which
are:
LC/MS (method D): ESI+ [M+H]+: m/z 259 tr (min)=0.86
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.71 (s, 3H),
3.43 (m, 2H), 3.57 (m, 1H), 3.96 (m, 1H), 4.97 (m, 1H), 7.29 (m,
5H).
[.alpha.].sub.D.sup.25 at 589 nm=-77.6.+-.1.4.degree. (c=1.818
mg/0.5 mL DMSO) for
(S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-meth-
ylpropionitrile
Step 7.3:
(R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-p-
henylethanol
##STR00048## 65.10 mL (65.10 mmol) of a 1 M solution of lithium
aluminum hydride in tetrahydrofuran are added to a solution, cooled
to 2.degree. C., of 16.80 g (65.10 mmol) of
(S)-3,3,3-trifluoro-2-((R)-2-hydroxy-1-phenylethylamino)-2-methylpropioni-
trile in 50 mL of anhydrous tetrahydrofuran in a three-necked flask
under argon. At the end of the addition, the reaction mixture is
allowed to warm to room temperature and is then stirred overnight.
The mixture obtained is cooled to 0.degree. C., followed by very
slow dropwise addition of 12 mL of water. Substantial evolution of
gas and a temperature rise to 4.degree. C. are observed. 12 mL of
15% potassium hydroxide and then 25 mL of water are added to the
resulting mixture, maintained at 0.degree. C. The white precipitate
formed is filtered off and the filtrate obtained is dried over
magnesium sulfate and then concentrated under reduced pressure to
give 10.50 g of
(R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenyletha-
nol, the characteristics of which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 263 tr (min)=0.43
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 0.90 (s, 3H),
2.48 (m, 2H), 2.72 (m, 2H), 3.31 (m, 4H), 3.95 (m, 1H), 7.27 (m,
5H).
[.alpha.].sub.D.sup.25 at 589 nm=-51.2.+-.1.3.degree. (c=1.576
mg/0.5 mL DMSO)
Step 7.4: (S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine
##STR00049##
A mixture of 10.50 g (70 mmol) of
(R)-2-((S)-1-aminomethyl-2,2,2-trifluoro-1-methylethylamino)-2-phenyletha-
nol in methanol, 4.5 mL (68 mmol) of methanesulfonic acid and 1.50
g of Pd(OH).sub.2/C (20% w/w) is hydrogenated at 25.degree. C. in
an autoclave, under a hydrogen pressure of 5 bar, for 24 hours. The
mixture obtained is then filtered and the filtrate is evaporated to
dryness. The oil obtained is taken up in 3 M hydrochloric acid
solution (42 mL). The mixture obtained is extracted with ethyl
ether. Ethyl ether and 15 mL of 35% sodium hydroxide are then added
to the aqueous phase, to pH 12. The aqueous phase is then separated
out by settling and extracted with 3 times 200 mL of ethyl ether.
The organic phases are combined, dried over magnesium sulfate,
filtered and then concentrated under vacuum to give 4.50 g of
(S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in the form of a
pale yellow oil, the characteristics of which are as follows:
LC/MS (method E): ESI+ [M+H]+: m/z 143 tr (min)=0.34
.sup.1H NMR (300 MHz, DMSO-d.sub.6): 1.10 (s, 3H), 1.60-1.85 (bs,
2H), 2.48 (d, 1H), 2.72 (d, 1H), 3.20-3.50 (bs, 2H).
[.alpha.].sub.D.sup.25 at 589 nm=-4.3.+-.0.6.degree. (c=1.778
mg/0.5 mL DMSO)
Step 7.5:
(S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine
hydrobromide
##STR00050## 11.60 mL (34.90 mmol) of cyanogen bromide dissolved in
dichloromethane are added portionwise to a solution, cooled to
4.degree. C., of 4.50 g (31.70 mmol) of
(S)-3,3,3-trifluoro-2-methylpropane-1,2-diamine in 20 mL of
acetonitrile, while maintaining the temperature between 5 and
10.degree. C. At the end of the addition, the reaction mixture is
left at 5.degree. C. for 30 minutes. The mixture obtained is then
stirred at room temperature overnight. The resulting mixture is
then concentrated under vacuum. The residue obtained is taken up
twice with ethanol and then twice with toluene, and evaporated to
dryness each time. The solid obtained is triturated with ethyl
ether and then filtered off to give 4.50 g of
(S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine
hydrobromide in the form of a white solid, the characteristics of
which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 168 tr (min)=0.14
.sup.1H NMR (300 MHz, DMSO-d.sub.6): 1.52 (s, 3H), 3.57 (m, 1H),
3.81 (m, 1H), 7.45 (s, 2H), 8.09 (s, 1H), 9.45 (s, 1H).
[.alpha.].sub.D.sup.25 at 589 nm: -5.2.+-.0.3.degree. (c=4.909
mg/0.5 mL DMSO)
Step 7.6:
(S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[-
1,2-a]pyrimidin-5-one
##STR00051## 36.90 g (148.76 mmol) of
(S)-4-methyl-4-trifluoromethyl-4,5-dihydro-1H-imidazol-2-ylamine
hydrobromide and 24.10 g (446 mmol) of sodium methoxide are added
to a mixture of 29.50 g (216.43 mmol) of diethyl malonate in 200 mL
of methanol. The resulting mixture is refluxed for 18 hours. After
cooling, the mixture obtained is concentrated to dryness under
vacuum. 65 mL of cold water are added to the residue obtained, to
obtain a thick suspension, to which is added 25% hydrochloric acid
to pH 5. The resulting suspension is stirred in an ice bath for 3
hours and then filtered. The insoluble matter obtained is rinsed
with water and then dried to give 37.60 g of
(S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one in the form of a white solid, the characteristics of
which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 236 tr (min)=0.32
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.53 (s, 3H), 3.95 (m, 1H),
4.10 (m, 1H), 4.79 (s, 1H), 5.80-7.01 (bs, 1H), 9.09 (s, 1H).
[.alpha.].sub.D.sup.25 at 589 nm=-5.6.+-.0.6.degree. (c=1.789
mg/0.5 mL DMSO)
Step 7.7:
(S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1-
,2-a]pyrimidin-5-one
##STR00052## 41.60 mL (446.50 mmol) of phosphorus oxychloride are
added, at room temperature and under an argon atmosphere, to a
suspension of 35 g (148.80 mmol) of
(S)-7-hydroxy-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one in 350 mL of 1,2-dichloroethane. The resulting mixture
is then heated at 70.degree. C. for 4 hours. After cooling, the
reaction mixture is evaporated to dryness under vacuum. The residue
obtained is taken up in 35 mL of cold water and 500 mL of ethyl
acetate. 32% sodium hydroxide is added to the mixture obtained, to
pH=6-7. The organic phase is then separated out and then dried over
magnesium sulfate, filtered and concentrated under reduced pressure
to give 20 g of
(S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyri-
midin-5-one, the characteristics of which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 254 tr (min)=0.51
.sup.1H NMR (400 MHz, DMSO-d.sub.6): 1.57 (s, 3H), 4.00 (d, 1H),
4.21 (d, 1H), 5.84 (s, 1H), 9.64 (s, 1H).
[.alpha.].sub.D.sup.25 at 589 nm=-64.8.+-.1.10 (c=2.2 mg/0.5 mL
DMSO)
Step 7.8:
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-tri-
fluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
##STR00053##
1 g (3.84 mmol) of
(S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyri-
midin-5-one and 844.18 mg (5.91 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 1.38 mL (9.86
mmol) of triethylamine are added. The tube is sealed and heated at
140.degree. C. in an oil bath for 4 hours. After cooling, the crude
product is purified by chromatography on silica gel (eluent: 95/5
EtOAc/MeOH). After evaporating the fractions under reduced
pressure, 750 mg of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are obtained, the
characteristics of which are as follows:
LC/MS (method G): ESI+: [M+H]+: m/z 317 tr (min)=1.34
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.34 (s, 3H),
1.65 (m, 2H), 3.13 (m, 2H), 3.43 (m, 1H), 3.53 (m, 1H), 3.72 (d,
1H), 3.89 (d, 1H), 4.1-4.81 (bs, 3H), 8.77 (s, 1H).
Step 7.9:
2-methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-
-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo-
[1,2-a]pyrimidin-5-one
##STR00054##
150 mg (0.474 mmol) of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 5 mL of DMF
are added to a suspension of 50.08 mg (1.04 mmol) of sodium hydride
in 5 mL of DMF. The reaction mixture is placed under magnetic
stirring at room temperature for 15 minutes. A solution of 153.88
mg (0.521 mmol) of 3-(bromoacetyl)pyridine hydrobromide in 5 mL of
DMF is added dropwise to the reaction medium. The reaction is
stirred at room temperature overnight. The reaction medium is
evaporated to dryness. The crude product is taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH)
to give 100 mg of
2-methyl-1-[2-(5-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.52
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (s, 3H),
1.71 (m, 2H), 2.4 (s, 3H), 3-3.2 (m, 2H), 3.42 (s, 2H), 4 (d, 1H),
4.24 (d, 1H), 4.52 (t, 3H) 4.81 (d, 1H), 5.12 (d, 1H), 8.19 (s,
1H), 8.67 (s, 1H), 8.99 (s, 1H).
EXAMPLE 8
2-methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimid-
in-5-one (Compound 26)
##STR00055##
Step 8.1: 5-(2-bromoethyl)-4-methylthiazole
##STR00056##
1 g (6.98 mmol) of 2-(4-methylthiazol-5-yl)ethanol is dissolved in
15 mL of dichloromethane. The solution is cooled to 0.degree. C.
When the temperature is reached, 1.85 g (6.98 mmol) of
triphenylphosphine are added, followed by portionwise addition of
1.30 g (6.98 mmol) of N-bromosuccinimide. After stirring for 2
hours at 0.degree. C., the mixture is evaporated to dryness. The
residue is purified by chromatography on silica gel (eluent: 50/50
EtOAc/heptane) to give 900 mg of 5-(2-bromoethyl)-4-methylthiazole,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 206 tr (min)=1.52
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.42 (s, 3H)
3.3-3.35 (t, 2H) 3.5-3.55 (t, 2H) 8.62 (s, 1H)
Step 8.2:
2-methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-
-a]pyrimidin-5-one
##STR00057##
150 mg (0.474 mmol) of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 5 mL of DMF
are added to a suspension of 45.53 mg (0.95 mmol) of sodium hydride
in 5 mL of DMF. The reaction mixture is heated for 15 minutes at
80.degree. C. A solution of 293.24 mg (1.42 mmol) of
5-(2-bromoethyl)-4-methylthiazole in 5 mL of DMF is added dropwise
to the reaction medium. The reaction is heated at 80.degree. C.
overnight. The reaction medium is evaporated to dryness. The crude
product is taken up in water and extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 95/5 EtOAc/MeOH) to give 45 mg of
2-methyl-1-[2-(4-methylthiazol-5-yl)ethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimi-
din-5-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 442 tr (min)=0.56
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.55 (s, 3H),
1.86 (m, 2H), 2.34 (s, 3H), 3-3.48 (m, 7H), 3.6 (m, 1H), 3.66 (m,
1H), 3.76 (m, 1H), 3.86 (d, 1H), 4.13 (d, 1H), 4.66 (s, 1H), 8.86
(s, 1H).
EXAMPLE 9
(8S)-9-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one (Compound 19)
##STR00058##
Step 9.1: 1-(2-methylpyrid-3-yl)ethanone
##STR00059##
The following are successively introduced into a microwave
tube:
469.80 .mu.l (4.07 mmol) of 3-bromo-5-methylpyridine in 20 mL of
H.sub.2O/DMF: (1/3: v/v), 2.03 mL (5.70 mmol) of
tributyl(1-ethoxyvinyl)tin, 57.12 mg (81.38 mmol) of
bis(triphenylphosphine)palladium(II) chloride, 1.12 g (8.14 mmol)
of potassium carbonate. After irradiating with microwaves for 1
hour at 110.degree. C., the reaction mixture is evaporated to
dryness and the residue is taken up in water and extracted with
ethyl acetate. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is taken up in a solution
consisting of 6 mL of methanol and 1 mL of 1 N hydrochloric acid.
After stirring overnight at room temperature, the reaction mixture
is evaporated to dryness and the residue is taken up in saturated
aqueous NaHCO.sub.3 solution and extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 50/50 EtOAc/heptane) to give 160 mg of
1-(2-methylpyrid-3-yl)ethanone, the characteristics of which are as
follows:
LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min)=0.38
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.58 (s, 3H),
2.61 (s, 3H), 7.38 (m, 1H), 8.2 (m, 1H), 8.57 (m, 1H).
Step 9.2: 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide
##STR00060##
150 mg (1.11 mmol) of 1-(2-methylpyrid-3-yl)ethanone are dissolved
in 10 mL of glacial acetic acid. 365 .mu.l (2.22 mmol) of
hydrobromic acid and 63 .mu.l (1.22 mmol) of bromine are added to
the medium. The reaction mixture is placed under magnetic stirring
at room temperature for 1 hour. Ethyl ether is added to the
solution until a precipitate appears. The precipitate corresponding
to 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide is filtered
off, washed with ethyl ether and dried. The 280 mg of product
obtained have the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min)=0.72
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.73 (s, 3H),
5 (s, 2H), 7.86 (m, 1H), 8.76 (m, 1H), 8.86 (m, 1H).
Step 9.3:
(8S)-9-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one
##STR00061##
140 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are
added to a suspension of 46.74 mg (0.97 mmol) of sodium hydride in
4 mL of DMF. The reaction mixture is placed under magnetic stirring
at room temperature for 15 minutes. A solution of 143.62 mg (0.443
mmol) of 2-bromo-1-(2-methylpyrid-3-yl)ethanone hydrobromide in 3
mL of DMF is added dropwise to the reaction medium. The reaction is
stirred at room temperature for 1 hour. The reaction medium is
evaporated to dryness. The crude product is taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH)
to give 100 mg of
(8S)-9-[2-(2-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.48
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.71 (m, 2H),
2.25 (m, 1H), 2.43 (m, 1H), 2.6 (s, 3H), 3.1-3.15 (m, 2H), 3.28 (m,
1H), 3.33-3.52 (bs, 2H), 4.37 (m, 1H), 4.52 (d, 2H), 4.59 (m, 1H),
4.64 (d, 1H), 4.69 (s, 1H), 5.5 (d, 1H), 7.4 (m, 1H), 8.28 (m, 1H),
8.61 (m, 1H).
EXAMPLE 10
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one (Compound 43)
##STR00062##
Step 10.1: 2-bromo-1-(4-methylthiazol-5-yl)ethanone
hydrobromide
##STR00063##
220 mg (1.56 mmol) of 1-(4-methylthiazol-5-yl)ethanone are
dissolved in 10 mL of glacial acetic acid. 769 .mu.l (4.67 mmol) of
hydrobromic acid and 88 .mu.l (1.71 mmol) of bromine are added to
the medium. The reaction mixture is placed under magnetic stirring
at room temperature for 2 hours. Ethyl ether is added to the
solution until a precipitate appears. The precipitate corresponding
to 2-bromo-1-(4-methylthiazol-5-yl)ethanone hydrobromide is
filtered off, washed with ethyl ether and dried. The 350 mg of
product obtained have the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 220 tr (min)=1.32
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.67 (s, 3H),
4.79 (s, 2H), 9.31 (s, 1H).
Step 10.2:
(8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluo-
romethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00064##
A suspension of 150 mg (0.591 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 213.64
mg (0.709 mmol) of 2-bromo-1-(4-methylthiazol-5-yl)ethanone
hydrobromide are then added. After stirring overnight at room
temperature, the reaction mixture is evaporated and the residue is
taken up in water and extracted with ethyl acetate. The organic
phase is dried over magnesium sulfate and evaporated to dryness to
give 190 mg of
(8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6-
,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 393 tr (min)=1.95
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.3 (m, 1H),
2.49 (s, 1H), 2.72 (s, 3H), 3.37 (m, 1H), 4.4 (m, 1H), 4.77 (m,
1H), 4.81 (s, 1H), 5.22 (d, 1H), 5.96 (s, 1H), 9.58 (s, 1H).
Step 10.3:
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5--
azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,-
2-a]pyrimidin-4-one
##STR00065##
170 mg (0.511 mmol) of
(8S)-2-chloro-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-8-trifluoromethyl-6-
,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 70.42 mg (0.52
mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are
mixed together. The powder obtained is placed in a tube and 151
.mu.l (1.08 mmol) of triethylamine are added. The tube is sealed
and heated at 130.degree. C. in an oil bath for 3 hours. The crude
product obtained is taken up in water and extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of
(8S)-9-[2-(4-methylthiazol-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo-
[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 456 tr (min)=0.55
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.69 (m, 2H),
2.28 (m, 1H), 2.43 (m, 1H), 2.7 (s, 3H), 2.98 (d, 1H), 3.12 (d,
1H), 3.21-3.33 (m, 3H), 4.37 (m, 1H), 4.42 (s, 1H), 4.5 (s, 1H),
4.55-4.62 (m, 2H), 4.67 (s, 1H), 5.22 (d, 1H), 9.19 (s, 1H).
EXAMPLE 11
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydropy-
ran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one (Compound 62)
##STR00066##
Step 11.1:
(8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluo-
romethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00067##
A suspension of 150 mg (0.591 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 578.13 mg (1.77 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 146.97
mg (0.709 mmol) of 2-bromo-1-(tetrahydropyran-4-yl)ethanone are
then added. After stirring overnight at room temperature, the
reaction mixture is evaporated and the residue is taken up in water
and extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness to give 220 mg of
(8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6-
,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 380 tr (min)=1.94
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.58-2.04 (m,
2H), 2.37 (m, 1H), 2.5 (m, 1H), 2.76 (m, 1H), 3.5 (4H), 3.9 (d,
1H), 3.96-4.02 (m, 4H), 4.6 (m, 1H), 5.25 (d, 1H), 5.99 (s,
1H).
Step 11.2:
(8S)-2-(1S,4S)-2-Oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(t-
etrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,-
2-a]pyrimidin-4-one
##STR00068##
220 mg (0.58 mmol) of
(8S)-2-chloro-9-[2-oxo-2-(tetrahydropyran-4-yl)ethyl]-8-trifluoromethyl-6-
,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69
mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are
mixed together. The powder obtained is placed in a tube and 202
.mu.l (1.45 mmol) of triethylamine are added. The tube is sealed
and heated at 130.degree. C. in an oil bath for 3 hours. The crude
product obtained is taken up in water and extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 EtOAc/MeOH) to give 220 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-oxo-2-(tetrahydrop-
yran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimi-
din-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 443 tr (min)=0.52
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.49 (m, 1H),
1.52 (m, 1H), 1.7 (m, 2H), 1.79 (bs, 2H), 2.15 (m, 1H), 2.36 (m,
1H), 2.7 (m, 1H), 2.84-3.25 (bs, 3H), 3.31-3.59 (bs, 3H), 3.65 (d,
1H), 3.86 (m, 2H), 4.17 (d, 1H), 4.3 (m, 1H), 4.35-5.3 (bs,
5H).
EXAMPLE 12
(8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one (Compound 20)
##STR00069##
Step 12.1: 1-(4-methylpyrid-3-yl)ethanone
##STR00070##
671 .mu.l (5.81 mmol) of 3-bromo-4-methylpyridine in 15 mL of
H.sub.2O/DMF (1/4: v/v), 1.93 mL (14.53 mmol) of N-butyl vinyl
ether, 39.15 mg (0.17 mmol) of palladium(II) acetate, 163.14 mg
(0.38 mmol) of 1,3-bis(diphenylphosphino)propane and 973.84 mg
(6.98 mmol) of potassium carbonate are placed in a microwave tube.
After irradiating with microwaves at 120.degree. C. for 2 hours, 20
mL of 5% hydrochloric acid solution are added. The reaction mixture
is stirred for 1 hour at room temperature and then basified with
potassium carbonate and extracted with ethyl acetate. The organic
phase is dried over magnesium sulfate and evaporated to dryness.
The residue is purified by chromatography on silica gel (eluent:
50/50 EtOAc/heptane) to give 320 mg of
1-(4-methylpyrid-3-yl)ethanone, the characteristics of which are as
follows:
LC/MS (method G): ESI+ [M+H]+: m/z 136 tr (min)=0.56
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.46 (s, 3H),
2.62 (s, 3H), 7.35 (d, 1H), 8.56 (d, 1H), 9 (s, 1H).
Step 12.2: 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide
##STR00071##
300 mg (2.22 mmol) of 1-(4-methylpyrid-3-yl)ethanone are dissolved
in 20 mL of glacial acetic acid. 730 .mu.l (4.44 mmol) of
hydrobromic acid and 126 .mu.l (2.44 mmol) of bromine are added to
the medium. The reaction mixture is placed under magnetic stirring
at room temperature for 2 hours. Ethyl ether is added to the
solution until a precipitate appears. The precipitate corresponding
to 2-bromo-1-(4-methylpyrid-3-yl)ethanone hydrobromide is filtered
off, washed with ethyl ether and dried. The 550 mg of product
obtained have the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min)=1.01
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.59 (s, 3H),
5.04 (s, 2H), 7.85 (d, 1H), 8.84 (d, 1H), 9.25 (s, 1H).
Step 12.3: (8S)-2-chloro-9-[2-(4-methyl
pyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one
##STR00072##
A suspension of 100 mg (0.394 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 385.42 mg (1.18 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 139.57
mg (0.473 mmol) of 2-bromo-1-(4-methylpyrid-3-yl)ethanone
hydrobromide are then added. After stirring overnight at room
temperature, the reaction mixture is evaporated and the residue is
taken up in water and extracted with ethyl acetate. The organic
phase is dried over magnesium sulfate and evaporated to dryness to
give 140 mg of
(8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min)=1.87
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.27 (m, 1H),
2.44 (s, 3H), 2.5 (m, 1H), 3.4 (m, 1H), 4.4 (m, 1H), 4.77 (m, 1H),
4.86 (d, 1H), 5.32 (d, 1H), 5.97 (s, 1H), 7.4 (d, 1H), 8.6 (d, 1H),
9 (s, 1H).
Step 12.4: (8S)-9-[2-(4-methyl
pyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-tr-
ifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00073##
140 mg (0.36 mmol) of
(8S)-2-chloro-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 94.26 mg (0.69
mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are
mixed together. The powder obtained is placed in a tube and 126
.mu.l (0.90 mmol) of triethylamine are added. The tube is sealed
and heated at 120.degree. C. in an oil bath for 2 hours. The crude
product obtained is taken up in water and extracted with ethyl
acetate. The organic phase is dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 EtOAc/MeOH) to give 120 mg of
(8S)-9-[2-(4-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.48
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.7 (m, 2H),
2.25 (m, 1H), 2.42 (m, 1H), 2.45 (s, 3H), 3-3.2 (m, 2H), 3.24-3.53
(bs, 3H), 3.36 (m, 1H), 4.51 (s, 1H), 4.54 (s, 1H), 4.59 (m, 1H),
4.65-4.76 (m, 2H), 5.55 (d, 1H), 7.37 (d, 1H), 8.59 (d, 1H), 9.05
(s, 1H).
EXAMPLE 13
(8S)-9-(2-methyl-2-pyrid-4-yl
propyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,-
7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Compound 1)
##STR00074##
Step 13.1: ethyl 2-methyl-2-pyrid-4-ylpropionate
##STR00075##
The reaction is performed under argon: 2 g (12.12 mmol) of ethyl
pyrid-4-ylacetate are dissolved in 30 mL of DMF. After addition of
15.25 mL (15.15 mmol) of a 1 M solution of lithium
bis(trimethylsilyl)amide in THF, the reaction mixture is stirred at
room temperature for 30 minutes. 1.21 mL (19.39 mmol) of
iodomethane are then added gently, and the solution obtained is
stirred at room temperature for 1 hour 30 minutes. A second portion
of 15.25 mL (15.15 mmol) of a 1 M solution of lithium
bis(trimethylsilyl)amide in THF is added, and the mixture is
stirred at room temperature for 1 hour. A second portion of 1.21 mL
(19.39 mmol) of iodomethane is also added, and stirring is
continued for 2 hours at room temperature. The precipitate formed
is filtered off, the filtrate is evaporated to dryness and the
residue is taken up in dichloromethane. The organic phase is washed
with water and with aqueous ammonium chloride solution, dried and
evaporated to dryness to give 1.80 g of ethyl
2-methyl-2-pyrid-4-ylpropionate, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 194 tr (min)=1.03
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.11 (t, 3H),
1.49 (s, 6H), 4.09 (q, 2H), 7.31 (d, 2H), 8.52 (d, 2H).
Step 13.2: 2-methyl-2-pyrid-4-ylpropan-1-ol
##STR00076##
A solution of 1.58 g (7.36 mmol) of ethyl
2-methyl-2-pyrid-4-ylpropionate in 30 mL of THF is cooled to
10.degree. C. When the temperature is reached, 22.08 mL (22.08
mmol) of 1 M diisobutylaluminum hydride solution in toluene are
added dropwise. The reaction mixture is allowed to warm to room
temperature and is stirred overnight. 1 N hydrochloric acid
solution is added to the reaction medium, which is then extracted
with ethyl acetate. The organic phase is dried over magnesium
sulfate and evaporated to dryness to give 1.60 g of
2-methyl-2-pyrid-4-ylpropan-1-ol, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 152 tr (min)=0.40
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.19 (s, 6H),
3.42 (d, 2H), 4.76 (t, 1H), 7.34 (d, 2H), 8.44 (d, 2H).
Step 13.3: 2-methyl-2-pyrid-4-ylpropyl benzenesulfonate
##STR00077##
710 .mu.l (4.07 mmol) of N,N-diisopropylethylamine and 33.13 mg
(0.27 mmol) of 4-dimethyl amino pyridine are added to a solution of
410 mg (2.71 mmol) of 2-methyl-2-pyrid-4-ylpropan-1-ol in 10 mL of
dichloromethane. The mixture is cooled to 0.degree. C. and a
solution of 775.42 mg (4.07 mmol) of 4-methylbenzene-1-sulfonyl
chloride in 2 mL of dichloromethane is then added. After allowing
the reaction medium to warm to room temperature and stirring
overnight, it is washed with water and with saturated NaCl
solution. The organic phase is dried over magnesium sulfate and
evaporated to dryness to give 660 mg of 2-methyl-2-pyrid-4-ylpropyl
benzenesulfonate, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 306 tr (min)=1.49
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.22 (s, 6H),
2.43 (s, 3H), 4.11 (s, 2H), 7.27 (d, 2H), 7.42 (d, 2H), 7.66 (d,
2H), 8.43 (d, 2H).
Step 13.4: (8S)-9-(2-methyl-2-pyrid-4-yl
propyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,-
7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00078##
The following are placed in a tube: 130 mg (0.411 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 133.92 mg (0.411 mmol)
of cesium carbonate, 6.16 mg (0.041 mmol) of sodium iodide and
175.74 mg (0.575 mmol) of 2-methyl-2-pyrid-4-ylpropyl
benzenesulfonate in 5 mL of DMF. The reaction mixture is heated
overnight at 150.degree. C. in the sealed tube. After allowing the
mixture to cool to room temperature, the solvent is evaporated off.
The residue is taken up in ethyl acetate, washed with water, dried
over magnesium sulfate and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 EtOAc/MeOH)
to give 18 mg of
(8S)-9-(2-methyl-2-pyrid-4-ylpropyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]h-
ept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e, the characteristics of which are as follows:
LC/MS (method B): ESI+ [M+H]+: m/z 450 tr (min)=0.53
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.24 (s, 1H),
1.31 (s, 3H), 1.35 (s, 3H), 1.83 (m, 2H), 2.09 (m, 1H), 2.18 (m,
1H), 3.02 (m, 1H), 3.21 (m, 2H), 3.57 (m, 1H), 3.75 (m, 2H), 3.98
(m, 1H), 4.65 (m, 2H), 4.76 (d, 1H), 4.99 (m, 1H), 7.49 (s, 2H),
8.53 (s, 2H).
EXAMPLE 14
1-ethyl-3-{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-
-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phe-
nyl}urea (Compound 23)
##STR00079##
Step 14.1: tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate
##STR00080##
5 g (35.36 mmol) of 2-(4-aminophenyl)ethanol and 6.17 mL (35.36
mmol) of N,N-diisopropylethylamine are added to a solution of 8.49
g (38.89 mmol) of di-tert-butyl dicarbonate in 10 mL of dioxane.
After stirring for 4 hours at room temperature, the reaction
mixture is evaporated to dryness. The residue is taken up in ethyl
acetate and the solution is washed with 1 N hydrochloric acid
solution and then with water. The organic phase is dried over
magnesium sulfate and evaporated to dryness to give 7.85 g of
tert-butyl [4-(2-hydroxyethyl)phenyl]carbamate, the characteristics
of which are as follows:
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.47
(s, 9H), 2.65 (t, 2H), 3.54 (q, 2H), 4.60 (t, 1H), 7.07 (d, 2H),
7.33 (d, 2H), 9.13-9.3 (bs, 1H).
Step 14.2: tert-butyl [4-(2-bromoethyl)phenyl]carbamate
##STR00081##
8.68 g (33.08 mmol) of triphenylphosphine are added, under an argon
atmosphere, to a solution of 7.85 g (33.08 mmol) of tert-butyl
[4-(2-hydroxyethyl)phenyl]carbamate in 85 mL of dichloromethane.
The mixture is cooled to 0.degree. C. and 5.95 g (33.08 mmol) of
N-bromosuccinimide are added portionwise over 25 minutes. Stirring
is continued for 3 hours at 0.degree. C. The solvent is then
evaporated off, the oil obtained is taken up in ether and the
precipitate formed is filtered off and discarded. The filtrate is
evaporated and the residue is purified by chromatography on silica
gel (eluent: 10/90 EtOAc/heptane) to give 6.90 g of tert-butyl
[4-(2-bromoethyl)phenyl]carbamate, the characteristics of which are
as follows:
LC/MS (method G): ESI+ [M+Na]+: 322 tr (min)=2.46
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.47
(s, 9H), 3.04 (t, 2H), 3.68 (t, 2H), 7.15 (d, 2H), 7.38 (d, 2H),
9.29 (s, 1H).
Step 14.3: tert-butyl
{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluor-
omethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}carba-
mate
##STR00082##
300 mg (0.95 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are
added to a suspension of 75.87 mg (1.89 mmol) of sodium hydride in
2 mL of 2-methyltetrahydrofuran. The reaction mixture is placed
under magnetic stirring at room temperature for 10 minutes. A
solution of 569.48 mg (1.89 mmol) of tert-butyl
[4-(2-bromoethyl)phenyl]carbamate in 3 mL of DMF is added dropwise
to the reaction medium. The reaction is stirred at room temperature
overnight. The reaction medium is evaporated to dryness. The crude
product is taken up in water and extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 95/5 EtOAc/MeOH) to give 240 mg of tert-butyl
{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluor-
omethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}carba-
mate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 536 tr (min)=2.46
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.45 (s, 9H),
1.9 (s, 3H), 2.32 (m, 1H), 2.70-2.98 (m, 2H), 3.13 (m, 2H),
3.24-3.47 (bs, 2H), 3.7 (m, 1H), 3.77 (m, 1H), 4.17 (m, 2H), 4.47-5
(bs, 4H), 7.01 (d, 2H), 7.38 (d, 2H), 9.28 (s, 1H).
Step 14.4:
(8S)-9-[2-(4-aminophenyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one
##STR00083##
4 mL (17.93 mmol of a 4 N HCl/dioxane solution are added to a
solution of 240 mg (0.45 mmol) of tert-butyl
{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluor-
omethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]phenyl}carba-
mate. The reaction mixture is stirred for 1 hour 30 minutes at room
temperature. The solvent is evaporated off and the residue is taken
up in a methanol/dichloromethane mixture and then evaporated to
give 245 mg of
(8S)-9-[2-(4-aminophenyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 436 tr (min)=1.60
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.79-2.12 (m,
3H), 2.33 (m, 1H), 2.82-3.09 (m, 2H), 3.17 (m, 2H), 3.37 (m, 1H),
3.58 (s, 1H), 3.69 (m, 2H), 3.79 (d, 1H), 4.2 (m, 2H), 4.67 (bs,
3H), 7.33 (s, 4H), 9.8-10.6 (bs, 2H).
Step 14.5:
1-ethyl-3-{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-6-oxo-2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-y-
l)ethyl]phenyl}urea
##STR00084##
50 .mu.l (0.63 mmol) of ethyl isocyanate are added to a solution of
150 mg (0.32 mmol) of
(8S)-9-[2-(4-aminophenyl)ethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
and 139 .mu.l (0.79 mmol) of N,N-diisopropylethylamine in 1 mL of
dichloromethane. After stirring overnight at room temperature, the
solvent is evaporated off. The residue is taken up in ethyl acetate
and washed with water and with saturated aqueous NaCl solution. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by reverse-phase chromatography
(RP18 column) (eluent: 50/50 H.sub.2O/MeOH) to give 92 mg of
1-ethyl-3-{4-[2-((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo--
2-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]ph-
enyl}urea, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 507 tr (min)=0.6
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.05 (t, 3H),
1.88 (m, 3H), 2.31 (m, 1H), 2.78 (m, 1H), 2.9 (m, 1H), 3.1 (m, 4H),
3.36 (m, 2H), 3.71 (d, 1H), 3.79 (d, 1H), 4.18 (d, 2H), 4.55 (m,
1H), 4.6-5.1 (bs, 3H), 6 (t, 1H), 7 (d, 2H), 7.3 (d, 2H), 8.3 (s,
1H).
EXAMPLE 15
1-ethyl-3-(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-o-
xo-2-((S)-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]eth-
yl}phenyl)urea (Compound 24)
##STR00085##
Step 15.1: tert-butyl
(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-
-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl-
)carbamate
##STR00086##
A suspension of 300 mg (0.948 mmol) of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one and 309.05 mg
(0.948 mmol) of cesium carbonate in 5 mL of DMF is stirred at
85.degree. C. for 15 minutes. A solution of 284.74 mg (0.948 mmol)
of tert-butyl [4-(2-bromoethyl)phenyl]carbamate is added dropwise.
After reacting overnight at 85.degree. C., the mixture is
evaporated and the residue is taken up in water and extracted with
ethyl acetate. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 95/5 EtOAc/MeOH) to give 385
mg of tert-butyl
(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-
-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl-
)carbamate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 536 tr (min)=2.48
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.47 (s, 9H),
1.53 (s, 3H), 1.85 (s, 2H), 2.77 (m, 1H), 2.93 (m, 1H), 3.29-3.46
(m, 5H), 3.54 (m, 1H), 3.68 (m, 1H), 3.81 (m, 2H), 4.13 (m, 1H),
4.66 (s, 1H), 7.11 (d, 2H), 7.39 (d, 2H), 9.29 (s, 1H).
Step 15.2:
1-[2-(4-aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one
##STR00087##
1 mL of trifluoroacetic acid is added to a solution of 385 mg (0.72
mmol) of tert-butyl
(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-5-oxo-2-((S)-
-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}phenyl-
)carbamate in 4 mL of dichloromethane. After stirring for 1 hour at
room temperature, the solvent is evaporated off. The residue is
taken up in ethyl acetate and washed with saturated aqueous
NaHCO.sub.3 solution. The organic phase is dried over magnesium
sulfate and evaporated to dryness to give 275 mg of
1-[2-(4-aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-o-
ne, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min)=0.48
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.52 (s, 3H),
1.87 (m, 2H), 2.69 (m, 1H), 2.87 (m, 1H), 3.26-3.53 (bs, 6H), 3.68
(d, 1H), 3.78 (m, 2H), 4.10 (d, 1H), 4.66 (s, 1H), 4.92 (s, 2H),
6.5 (d, 2H), 6.87 (d, 2H).
Step 15.3:
1-ethyl-3-(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-5-oxo-2-((S)-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimid-
in-1-yl]ethyl}phenyl)urea
##STR00088##
104 .mu.l (1.29 mmol) of ethyl isocyanate are added to a solution
of 140 mg (0.32 mmol) of
1-[2-(4-aminophenyl)ethyl]-2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-o-
ne in 1 mL of dichloromethane. After stirring for 3 hours at room
temperature, the solvent is evaporated off. The residue is taken up
in ethyl acetate and washed with water and with saturated aqueous
NaCl solution. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by reverse-phase
chromatography (RP18 column) (eluent: 50/50 H.sub.2O/MeOH) to give
83 mg of
1-ethyl-3-(4-{2-[(1S,4S)-2-methyl-7-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-
-5-oxo-2-((S)-trifluoromethyl)-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl-
]ethyl}phenyl)urea, the characteristics of which are as
follows:
LC/MS (method A): ESI+ [M+H]+: m/z 507 tr (min)=0.6
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.08 (t, 3H),
1.55 (s, 3H), 1.88 (m, 2H), 2.82 (m, 1H), 2.97 (m, 1H), 3.12 (m,
2H), 3.19 (m, 1H), 3.39 (d, 1H), 3.43 (m, 1H), 3.58 (m, 1H), 3.7
(d, 1H), 3.78 (d, 1H), 3.82 (d, 1H), 4.12 (d, 1H), 4.58 (s, 1H),
4.64 (s, 1H), 4.82 (bs, 1H), 5.95 (m, 1H), 7.08 (d, 2H), 7.32 (d,
2H), 8.15 (s, 1H).
EXAMPLE 16
(8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1S-
,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahyd-
ropyrimido[1,2-a]pyrimidin-4-one (Compound 38)
##STR00089##
Step 16.1:
1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone
##STR00090##
The procedure used is the same as that of step 12.1.
800 mg (3.61 mmol) of
7-bromo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine were used in the
reaction. After purification by chromatography on silica gel
(eluent: 90/10 DCM/MeOH), 320 mg of
1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone were
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 179 tr (min)=0.66
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.42 (s, 3H),
3.47 (q, 2H), 4.12 (t, 2H), 7.3 (s, 1H), 7.77 (s, 1H), 8.28 (s,
1H).
Step 16.2:
2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanon- e
hydrobromide
##STR00091##
The procedure used is the same as that of step 12.2.
320 mg (1.80 mmol) of
1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone were used
in the reaction. After precipitation with ethyl ether and
filtration, 690 mg of
2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone
hydrobromide are obtained, the characteristics of which are as
follows:
LC/MS (method G): ESI+ [M+H]+: m/z 257 tr (min)=1.10
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 3.57 (t, 2H),
4.23 (t, 2H), 4.78 (s, 2H), 7.55 (s, 1H), 8.38 (s, 1H), 8.5-9 (bs,
1H).
Step 16.3:
(8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-y-
l)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one
##STR00092##
The procedure used is the same as that of step 12.3.
200 mg (0.79 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 319.86 mg (0.95 mmol) of
2-bromo-1-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)ethanone
hydrobromide were used in the reaction. After purification by
chromatography on silica gel (eluent: 90/10 DCM/MeOH), 110 mg of
(8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoet-
hyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
are obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 430 tr (min)=1.77
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.27 (m, 1H),
2.44 (s, 1H), 3.17 (d, 1H), 3.39 (m, 1H), 3.49 (s, 2H), 4.13 (m,
2H), 4.37 (m, 1H), 4.58-4.77 (m, 2H), 5.48 (d, 1H), 7.36 (s, 1H)
7.97 (s, 1H), 8.38 (s, 1H).
Step 16.4:
(8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoe-
thyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00093##
The procedure used is the same as that of step 12.4.
110 mg (0.25 mmol) of
(8S)-2-chloro-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoet-
hyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
and 41.64 mg (0.31 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride were used in
the reaction. After purification by passing through an RP18
reverse-phase column (eluent: from 100% H.sub.2O to 100% CH.sub.3CN
over 30 minutes), 30 mg of
(8S)-9-[2-(3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-7-yl)-2-oxoethyl]-2-(1-
S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahy-
dropyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics
of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 493 tr (min)=0.49
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (d, 1H),
1.72 (d, 1H), 2.25 (m, 1H), 2.4 (m, 1H), 2.99 (m, 1H), 3.13 (m,
1H), 3.2 (m, 1H), 3.26 (m, 2H), 3.49 (m, 2H), 4.13 (t, 2H) 4.36 (m,
1H), 4.41 (d, 1H), 4.48 (d, 2H) 4.52 (m, 1H), 4.63 (s, 1H), 5.52
(d, 1H), 7.36 (s, 1H), 7.57 (s, 1H), 8.37 (s, 1H).
EXAMPLE 17
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabic-
yclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one (Compound 47)
##STR00094##
Step 17.1:
N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide
##STR00095##
The procedure used is the same as that of step 4.1.
500 mg (2.44 mmol) of benzo[1,2,3]thiadiazole-5-carbonyl chloride
are used in the reaction. 620 mg of
N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide are
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 224 tr (min)=1.36
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 3.34 (s, 3H),
3.57 (s, 3H), 7.99 (d, 1H), 8.5 (d, 1H), 8.9 (s, 1H).
Step 17.2: 1-benzo[1,2,3]thiadiazol-5-ylethanone
##STR00096##
The procedure used is the same as that of step 4.2.
620 mg (2.78 mmol) of
N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide were used
in the reaction. The mixture is basified with aqueous 1 N NaOH
solution and extracted with ethyl acetate. The organic phase is
dried over magnesium sulfate and evaporated to dryness to give 430
mg of 1-benzo[1,2,3]thiadiazol-5-ylethanone, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 224 tr (min)=1.49
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.78 (s, 3H),
8.29 (d, 1H), 8.53 (d, 1H), 9.32 (s, 1H).
Step 17.3: 1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone
##STR00097##
The procedure used is the same as that of step 12.2.
430 mg (2.41 mmol) of 1-benzo[1,2,3]thiadiazol-5-ylethanone were
used in the reaction. The reaction mixture is evaporated to dryness
and taken up in dichloromethane. The organic phase is washed with
aqueous NaHCO.sub.3 solution and with saturated NaCl solution,
dried and evaporated to dryness to give 300 mg of
1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 257 tr (min)=1.71
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 5.19 (s, 2H),
8.31 (d, 1H), 8.57 (d, 1H), 9.43 (s, 1H).
Step 17.4:
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-tr-
ifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00098##
The procedure used is the same as that of step 12.3.
150 mg (0.59 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 167.25 mg (0.65 mmol) of
1-benzo[1,2,3]thiadiazol-5-yl-2-bromoethanone were used in the
reaction. After purification by chromatography on silica gel
(eluent: 90/10 DCM/MeOH), 210 mg of
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 430 tr (min)=2.29
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.32 (m, 1H),
2.42-2.62 (m, 2H), 3.36-3.48 (m, 1H), 4.42 (m, 1H), 4.8 (m, 1H),
5.14 (d, 1H), 5.76 (m, 1H), 8.35 (d, 1H), 8.61 (d, 1H), 9.51 (s,
1H).
Step 17.5:
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-o-
xa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimi-
do[1,2-a]pyrimidin-4-one
##STR00099##
The procedure used is the same as that of step 12.4.
210 mg (0.49 mmol) of
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-chloro-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 79.50 mg
(0.58 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
hydrochloride were used in the reaction. After purification by
chromatography on silica gel (eluent: 60/40 DCM/MeOH), 100 mg of
(8S)-9-(2-benzo[1,2,3]thiadiazol-5-yl-2-oxoethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one are obtained, the characteristics of which are as
follows:
LC/MS (method A): ESI+ [M+H]+: m/z 493 tr (min)=0.64
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.36-1.78 (bs,
2H), 2.27 (m, 1H), 2.45-2.5 (m, 2H), 2.75-3.25 (bs, 4H), 4.23-4.98
(bs, 6H), 5.9 (m, 1H), 8.34 (d, 1H), 8.58 (d, 1H), 9.5 (s, 1H).
EXAMPLE 18
(8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1-
]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4--
one (Compound 51)
##STR00100##
Step 18.1:
(8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromet-
hyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00101##
The procedure used is the same as that of step 12.3.
180 mg (0.71 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 145.39 mg (0.78 mmol) of
3-chloromethyl-1-methyl-1H-indazole were used in the reaction.
After purification by chromatography on silica gel (eluent: 80/20
DCM/MeOH), 250 mg of
(8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,-
9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained, the
characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 398 tr (min)=2.2
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.01 (m, 1H),
2.44 (m, 1H), 3.24-3.41 (m, 2H), 4.02 (s, 3H), 4.23 (m, 1H), 4.66
(d, 1H), 4.75 (m, 1H), 5.89 (d, 1H), 7.15 (t, 1H), 7.42 (t, 1H),
7.62 (d, 1H), 7.84 (d, 1H).
Step 18.2:
(8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one
##STR00102##
The procedure used is the same as that of step 12.4.
250 mg (0.63 mmol) of
(8S)-2-chloro-9-(1-methyl-1H-indazol-3-ylmethyl)-8-trifluoromethyl-6,7,8,-
9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 102.26 mg (0.75
mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride
were used in the reaction. After purification by chromatography on
silica gel (eluent: 60/40 DCM/MeOH), 230 mg of
(8S)-9-(1-methyl-1H-indazol-3-ylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.-
1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-
-one are obtained, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 461 tr (min)=0.68
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.75 (m, 2H),
2.08 (m, 1H), 2.4 (d, 1H), 2.6-3.3 (bs, 5H), 3.99 (s, 3H), 4.2 (m,
1H), 4.4-4.67 (t, 3H), 4.66-4.9 (bs, 2H), 5.89 (d, 1H), 7.11 (t,
1H), 7.39 (t, 1H), 7.58 (d, 1H), 7.73 (d, 1H).
EXAMPLE 19
(8S)-9-[2-(2-Cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one (Compound 52)
##STR00103##
Step 19.1: 5-bromo-2-cyclopropylmethoxypyrimidine
##STR00104##
A suspension of 607.92 mg (15.20 mmol) of sodium hydride in 50 mL
of THF is prepared under argon. A solution of 1.10 g (15.20 mmol)
of cyclopropanemethanol in 5 mL of THF is added dropwise. The
mixture is stirred for 50 minutes at room temperature. 1 g (5.07
mmol) of 5-bromo-2-chloropyrimidine in 5 mL of THF is then added.
The mixture is stirred at room temperature overnight. The reaction
mixture is taken up in water and extracted with ethyl acetate. The
organic phase is washed with aqueous NaHCO.sub.3 solution and with
saturated aqueous NaCl solution, dried and evaporated to dryness to
give 1.10 g of 5-bromo-2-cyclopropylmethoxypyrimidine,
corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 229 tr (min)=2.06
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 0.33 (m, 2H),
0.55 (m, 2H), 1.23 (m, 1H), 4.12 (d, 2H), 8.74 (s, 2H).
Step 19.2: 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine
##STR00105##
The following are successively introduced into a microwave
tube:
760 mg (3.32 mmol) of 5-bromo-2-cyclopropylmethoxypyrimidine in 15
mL of dioxane, 1.36 mL (3.82 mmol) of tributyl(1-ethoxyvinyl)tin,
58.22 mg (0.08 mmol) of bis(triphenylphosphine)palladium(II)
chloride, 1.12 g (7.30 mmol) of cesium fluoride. This mixture is
subjected to microwave irradiation at 110.degree. C. for 1 hour.
The reaction mixture is evaporated to dryness and the residue is
taken up in 100 mL of ethyl ether. A solution of 2.80 g of cesium
fluoride in 10 mL of water is added. After stirring for 1 hour at
room temperature, the mixture is filtered through Celite. The
filtrate is washed with aqueous NaHCO.sub.3 solution and then with
saturated NaCl solution. The organic phase is dried over magnesium
sulfate and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 10/90 EtOAc/heptane) to give
480 mg of 2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine, the
characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 221 tr (min)=2.34
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 0.35 (m, 2H),
0.57 (m, 2H), 0.86 (m, 1H), 1.34 (t, 3H), 3.91 (q, 2H), 4.16 (d,
2H), 4.35 (s, 1H), 4.85 (s, 1H), 8.78 (s, 2H).
Step 19.3:
2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone
##STR00106##
A solution of 480 mg (2.18 mmol) of
2-cyclopropylmethoxy-5-(1-ethoxyvinyl)pyrimidine in 8 mL of a
THF/H.sub.2O mixture: (6/2: v/v) is cooled to 0.degree. C. under
argon. After addition of 380.02 mg (2.11 mmol) of
N-bromosuccinimide, the reaction mixture is maintained at 0.degree.
C. for 1 hour. The solution obtained is taken up in ethyl acetate
and washed with aqueous NaHCO.sub.3 solution and then with
saturated NaCl solution. The organic phase is dried over magnesium
sulfate and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 80/20 DCM/MeOH) to give 410
mg of 2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone, the
characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 271 tr (min)=1.87
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 0.38 (m, 2H),
0.58 (m, 2H), 1.29 (m, 1H), 4.27 (d, 2H), 4.94 (s, 2H), 9.15 (s,
2H).
Step 19.4:
(8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoet-
hyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00107##
The procedure used is the same as that of step 12.3.
180 mg (0.71 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 211.66 mg (0.78 mmol) of
2-bromo-1-(2-cyclopropylmethoxypyrimidin-5-yl)ethanone were used in
the reaction. After purification by chromatography on silica gel
(eluent: 80/20 DCM/MeOH), 160 mg of
(8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-tri-
fluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 444 tr (min)=2.33
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 0.38 (m, 2H),
0.58 (m, 2H), 1.30 (m, 1H), 2.25 (m, 1H), 2.51 (m, 1H), 3.35 (m,
2H), 4.28 (d, 2H), 4.50 (m, 1H), 4.70 (m, 1H), 4.90 (d, 1H), 5.53
(d, 1H), 9.21 (s, 2H).
Step 19.5:
(8S)-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1-
S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahy-
dropyrimido[1,2-a]pyrimidin-4-one
##STR00108##
The procedure used is the same as that of step 12.4.
160 mg (0.36 mmol) of
(8S)-2-chloro-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-8-tri-
fluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and
58.66 mg (0.43 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
hydrochloride were used in the reaction. After purification by
chromatography on silica gel (eluent: 60/40 DCM/MeOH), 125 mg of
(8S)-9-[2-(2-cyclopropylmethoxypyrimidin-5-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one are obtained, the characteristics of which
are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 507 tr (min)=0.65
.sup.1H NMR spectrum (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.38
(m, 2H), 0.6 (m, 2H), 1.30 (m, 1H), 1.54-1.76 (m, 2H), 2.21 (m,
1H), 2.44 (m, 1H), 2.72-3.9 (bs, 5H), 4.28 (d, 2H), 4.31-4.98 (m,
6H), 5.67 (m, 1H), 9.22 (s, 2H).
EXAMPLE 20
(8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one (Compound 69)
##STR00109##
Step 20.1: 2-methyl-2H-pyrazole-3-carbonyl chloride
##STR00110##
A suspension of 800 mg (6.03 mmol) of
2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed
under argon and cooled to 0.degree. C. When the temperature is
reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic
amount of DMF are added. The reaction mixture is stirred at room
temperature for 2 hours and then evaporated to dryness and the
residue is taken up in DCM and evaporated again to give 850 mg of
2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of
which are as follows:
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 4.10 (s, 3H),
6.82 (s, 1H), 7.50 (s, 1H).
Step 20.2:
N-methoxy-N-methyl-2-methyl-2H-pyrazole-3-carboxamide
##STR00111##
The procedure used is the same as that of step 4.1.
850 mg (5.88 mmol) of 2-methyl-2H-pyrazole-3-carbonyl chloride are
used in the reaction. 890 mg of
N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide are
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 170 tr (min)=1.03
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 3.27 (s, 3H),
3.63 (s, 3H), 3.96 (s, 3H), 6.71 (s, 1H), 7.5 (s, 1H).
Step 20.3: 1-(2-methyl-2H-pyrazol-3-yl)ethanone
##STR00112##
The procedure used is the same as that of step 4.2.
890 mg (2.78 mmol) of
N-methoxy-N-methylbenzo[1,2,3]thiadiazole-5-carboxamide were used
in the reaction. The mixture is taken up in water and a few drops
of 1 N HCl, basified with aqueous 1 N NaOH solution and extracted
with ethyl acetate. The organic phase is dried over magnesium
sulfate and evaporated to dryness to give 570 mg of
1-(2-methyl-2H-pyrazol-3-yl)ethanone, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 125 tr (min)=0.93
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.5 (s, 3H) 4.04
(s, 3H) 7.13 (s, 1H) 7.53 (s, 1H)
Step 20.4: 1-(2-methyl-2H-pyrazol-3-yl)ethanone hydrobromide
##STR00113##
The procedure used is the same as that of step 12.2.
550 mg (4.43 mmol) of 1-(2-methyl-2H-pyrazol-3-yl)ethanone were
used in the reaction. The precipitate corresponding to
1-(2-methyl-2H-pyrazol-3-yl)ethanone hydrobromide is filtered off,
washed with ethyl ether and dried. The 1.15 g of product obtained
have the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 203 tr (min)=1.19
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 4.78 (s, 2H),
7.19 (s, 1H), 7.56 (s, 1H).
Step 20.5:
(8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-tri-
fluoromethyl-6,7,8,9-tetrahyhdropyrimido[1,2-a]pyrimidin-4-one
##STR00114##
The procedure used is the same as that of step 12.3.
180 mg (0.71 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 262 mg (0.92 mmol) of
1-(2-methyl-2H-pyrazol-3-yl)ethanone hydrobromide were used in the
reaction. After purification by chromatography on silica gel
(eluent: 80/20 DCM/MeOH), 230 mg of
(8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluorometh-
yl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one are obtained,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 376 tr (min)=1.98
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.28 (m, 1H),
3.4 (m, 2H), 4.06 (s, 3H), 4.39 (m, 1H), 4.66-4.84 (m, 2H), 5.41
(d, 1H), 5.96 (s, 1H), 7.36 (s, 1H), 7.63 (s, 1H).
Step 20.6:
(8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-ox-
a-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimid-
o[1,2-a]pyrimidin-4-one
##STR00115##
The procedure used is the same as that of step 12.4.
230 mg (0.61 mmol) of
(8S)-2-chloro-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-8-trifluorometh-
yl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 107.90 mg
(0.79 mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane
hydrochloride were used in the reaction. After purification by
chromatography on silica gel (eluent: 60/40 DCM/MeOH), 160 mg of
(8S)-9-[2-(2-methyl-2H-pyrazol-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabic-
yclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one are obtained, the characteristics of which are as
follows:
LC/MS (method A): ESI+ [M+H]+: m/z 439 tr (min)=0.54
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.48-1.8 (bs,
2H), 2.22 (m, 1H), 2.43 (d, 1H), 2.66-3.26 (bs, 5H), 4 (s, 3H),
4.28-4.88 (bs, 6H), 5.5 (d, 1H), 7.42 (s, 1H), 7.59 (s, 1H).
EXAMPLE 21
ethyl
{5-[2-((S)8-(1S,4S)-2-oxa-5-azabicyclo[2.2.]hept-5-yl-6-oxo-2-triflu-
oromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-y-
l}carbamate (Compound 57
##STR00116##
Step 21.1: 1-(6-aminopyrid-3-yl)ethanone
##STR00117##
2 g (11.57 mmol) of 1-(6-chloropyrid-3-yl)ethanone and 70 mL of
ammonium hydroxide are placed in a Parr reactor. The solution is
heated at 130.degree. C. overnight. The mixture obtained is
evaporated to dryness, and the residue is taken up in ethyl acetate
and washed with water and with saturated NaCl solution. The organic
phase is dried over sodium sulfate and evaporated to dryness to
give 1.14 g of 1-(6-aminopyrid-3-yl)ethanone, the characteristics
of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 137 tr (min)=0.35
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.41 (s, 3H),
6.45 (d, 1H), 6.88 (s, 2H), 7.86 (d, 1H), 8.58 (s, 1H).
Step 21.2: 2-bromo-1-(6-aminopyrid-3-yl)ethanone
##STR00118##
The procedure used is the same as that of step 12.2.
1.14 g (8.37 mmol) of 1-(6-aminopyrid-3-yl)ethanone were used in
the reaction. The reaction mixture is taken up in dichloromethane.
The organic phase is washed with aqueous K.sub.2CO.sub.3 solution
and with saturated NaCl solution, dried and evaporated to dryness.
After purification by chromatography on silica gel (eluent: 60/40
DCM/EtOAc), 530 mg of 2-bromo-1-(6-chloropyrid-3-yl)ethanone are
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 215 tr (min)=0.44
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 4.70 (s, 2H),
6.47 (d, 1H), 7.08 (s, 2H), 7.89 (d, 1H), 8.64 (s, 1H).
Step 21.3:
(8S)-9-[2-(6-aminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one
##STR00119##
500 mg (1.58 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 10 mL of DMF are
added to a suspension of 69.55 mg (1.74 mmol) of sodium hydride in
10 mL of DMF. The reaction mixture is placed under magnetic
stirring at room temperature for 15 minutes. A solution of 373.96
mg (1.74 mmol) of 2-bromo-1-(6-chloropyrid-3-yl)ethanone in 5 mL of
DMF is added dropwise to the reaction medium. The reaction is
stirred at room temperature for 2 hours. The reaction medium is
taken up in methanol and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 60/40 EtOAc/MeOH)
to give 530 mg of
(8S)-9-[2-(6-aminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 451 tr (min)=0.38
.sup.1H NMR (600 MHz, .delta. in ppm, CDCl.sub.3): 1.5-1.81 (m,
2H), 2.23 (m, 1H), 2.41 (m, 1H), 2.74-3.33 (bs, 5H), 4.23-4.76 (m,
6H), 5.6 (d, 1H), 6.47 (d, 1H), 6.97 (s, 2H), 7.92 (d, 1H) 8.71 (s,
1H).
Step 21.4: ethyl
{5-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamate
##STR00120##
168 .mu.l (1 mmol) of N,N-diisopropylethylamine and 65 .mu.l (0.66
mmol) of ethyl chloroformate are added to a solution of 150 mg
(0.33 mmol) of
(8S)-9-[2-(6-aminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one in 5 mL of DCM.
The heterogeneous mixture is stirred at room temperature for 15
minutes. The solution is taken up in DCM and washed with water and
with saturated NaCl solution. The organic phase is dried over
sodium sulfate and evaporated to dryness. The residue is dissolved
in 10 mL of ethanol, and aqueous 1 N NaOH solution is added. The
mixture is stirred for 30 minutes at room temperature and then
evaporated to dryness. The crude product is taken up in ethyl
acetate and washed with water and with saturated NaCl solution. The
organic phase is dried over sodium sulfate and evaporated to
dryness. After purification by chromatography on silica gel
(eluent: 60/40 DCM/MeOH), 120 mg of ethyl
{5-[2-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetyl]pyrid-2-yl}c-
arbamate are obtained, the characteristics of which are as
follows:
LC/MS (method A): ESI+ [M+H]+: m/z 523 tr (min)=0.6
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.27 (t, 3H),
1.61 (s, 1H), 1.7 (d, 1H), 2.24 (m, 1H), 2.44 (d, 1H), 2.57-3.17
(bs, 3H), 3.24 (m, 2H), 4.2 (q, 2H), 4.29-4.52 (m, 3H), 4.59 (m,
3H), 5.69 (d, 1H), 7.98 (d, 1H), 8.36 (d, 1H), 8.97 (s, 1H), 10.62
(s, 1H).
EXAMPLE 22
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-trifluorom-
ethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one (Compound
84)
##STR00121##
Step 22.1:
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,-
7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00122##
500 mg (1.97 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, 884 mg (5.91 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane and
820 .mu.l (5.91 mmol) of triethylamine are placed in a microwave
tube. The mixture is irradiated for 10 minutes at 150.degree. C.
The reaction medium is purified directly by passing through an RP18
reverse-phase column (eluent: H.sub.2O: 100% to CH.sub.3CN: 100%)
to give 600 mg of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetr-
ahydropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which
are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 331 tr (min)=0.53
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.66 (m, 2H),
1.81 (m, 2H), 2.09 (m, 1H), 2.2 (m, 1H), 2.89 (d, 2H), 3.34 (m,
1H), 3.75 (m, 2H), 4.14 (m, 1H), 4.26 (s, 1H), 4.37 (s, 2H), 4.84
(s, 1H), 8.17 (s, 1H).
Step 22.2:
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00123##
A solution of 200 mg (0.61 mmol) of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetr-
ahydropyrimido[1,2-a]pyrimidin-4-one and 790 mg (2.42 mmol) of
cesium carbonate in 10 mL of DMF is heated at 90.degree. C. for 10
minutes. After addition of 600 .mu.l (1.21 mmol) of
(3-bromopropyl)benzene, the reaction is continued for 2 hours at
90.degree. C. The solvent is evaporated off. The residue is
purified by RP18 reverse-phase chromatography (eluent: H.sub.2O
100% to CH.sub.3CN 100%) to give 100 mg of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(3-phenylpropyl)-8-triflu-
oromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, the
characteristics of which are as follows:
LC/MS (method B): ESI+ [M+H]+: m/z 449 tr (min)=0.85
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.57 (m, 2H),
1.79 (m, 3H), 2 (m, 2H), 2.31 (d, 1H), 2.62 (m, 2H), 2.8 (d, 2H),
3.13 (m, 2H), 3.53 (m, 2H), 3.94 (m, 1H), 4.15 (m, 1H), 4.31 (s,
2H), 4.62 (m, 1H), 4.82 (s, 1H), 7.18 (m, 3H), 7.27 (m, 2H).
EXAMPLE 23
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8-t-
rifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 75)
##STR00124##
A solution of 200 mg (0.61 mmol) of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetr-
ahydropyrimido[1,2-a]pyrimidin-4-one and 1.18 g (3.63 mmol) of
cesium carbonate in 10 mL of DMF is heated at 90.degree. C. for 10
minutes. The mixture is cooled to 0.degree. C. and 340 mg (1.21
mmol) of 2-bromo-1-pyrid-4-ylethanone are then added. The reaction
is continued for 2 hours at room temperature. The solvent is
evaporated off. The residue is purified by chromatography on a
column of silica (eluent: 90/10 DCM/MeOH). The isolated fraction is
recrystallized from acetonitrile to give 16 mg of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-9-(2-oxo-2-pyrid-4-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method B): ESI+ [M+H]+: m/z 450 tr (min)=0.55
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.32 (m, 1H)
1.5 (m, 1H) 1.62 (m, 2H) 2.2 (m, 1H) 2.42 (d, 1H) 2.51 (d, 1H) 2.69
(d, 1H) 3.2 (m, 1H) 3.38 (d, 2H) 4.05 (d, 2H) 4.31 (d, 1H) 4.61 (m,
1H) 4.85 (s, 2H) 5.45 (d, 1H) 7.89 (s, 2H) 8.85 (s, 2H)
EXAMPLE 24
(8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 80)
##STR00125##
200 mg (0.61 mmol) of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetr-
ahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a
suspension of 60 mg (1.51 mmol) of sodium hydride in 5 mL of DMF.
The reaction mixture is heated at 50.degree. C. for 10 minutes.
After addition of 142 mg (0.91 mmol) of
(S)-2-chloro-1-phenylethanol, the reaction is continued at
90.degree. C. overnight. The reaction medium is evaporated to
dryness. The residue is purified by chromatography on a column of
silica (eluent: 90/10 DCM/MeOH). The isolated fraction is
recrystallized from acetonitrile to give 33 mg of
(8S)-9-((S)-2-hydroxy-2-phenylethyl)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl-
)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method B): ESI+ [M+H]+: m/z 451 tr (min)=0.68
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.70 (m, 2H)
1.84 (m, 2H) 2.25 (m, 1H) 2.4 (m, 1H) 3.02 (m, 3H) 3.2 (m, 1H) 3.77
(m, 2H) 4.26 (m, 2H) 4.41 (s, 2H) 4.80 (m, 1H) 4.92 (s, 1H) 5.01
(m, 1H) 5.71 (d, 1H) 7.37 (m, 5H)
EXAMPLE 25
(8S)-9-[2-(6-dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabic-
yclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one (Compound 6)
##STR00126##
Step 25.1: 1-(6-dimethylaminopyrid-3-yl)ethanone
##STR00127##
500 mg (2.89 mmol) of 1-(6-chloropyrid-3-yl)ethanone, 2 mL of
ethanol and 7.23 mL (14.46 mmol) of 2 M dimethylamine in
tetrahydrofuran are placed in a 20 mL microwave reactor. The
solution is irradiated with microwaves for 10 minutes at
130.degree. C. The mixture obtained is taken up in water and
extracted with ethyl acetate. The organic phase is dried over
sodium sulfate and evaporated to dryness to give 470 mg of
1-(6-dimethylaminopyrid-3-yl)ethanone, the characteristics of which
are as follows:
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 2.44 (s, 3H),
3.12 (s, 6H), 6.68 (d, 1H), 7.96 (d, 1H), 8.72 (s, 1H).
Step 25.2: 2-bromo-1-(6-dimethylaminopyrid-3-yl)ethanone
hydrobromide
##STR00128##
The procedure used is the same as that of step 12.2.
514 mg (3.13 mmol) of 1-(6-dimethylaminopyrid-3-yl)ethanone were
used in the reaction. The precipitate corresponding to
2-bromo-1-(6-dimethylaminopyrid-3-yl)ethanone hydrobromide is
filtered off, washed with ether and dried. The 950 mg of product
obtained have the following characteristics:
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 3.22 (s, 6H),
4.80 (s, 2H), 6.95 (d, 1H), 8.10 (d, 1H), 8.68 (s, 1H).
Step 25.3:
(8S)-9-[2-(6-dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-o-
xa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimi-
do[1,2-a]pyrimidin-4-one
##STR00129##
100 mg (0.32 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 2 mL of DMF are
added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride in
3 mL of DMF. The reaction mixture is placed under magnetic stirring
at room temperature for 15 minutes. A solution of 84.55 mg (0.35
mmol) of 2-bromo-1-(6-dimethylaminopyrid-3-yl)ethanone in 5 mL of
DMF is added dropwise to the reaction medium. The reaction is
stirred at room temperature for 5 minutes. The reaction medium is
taken up in ethanol and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to
give 34 mg of
(8S)-9-[2-(6-dimethylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 479 tr (min)=0.48
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62 (bs, 1H),
1.73 (d, 1H), 2.24 (m, 1H), 2.42 (m, 1H), 2.66-3.27 (m, 11H),
4.05-4.96 (m, 6H), 5.63 (d, 1H), 6.71 (d, 1H), 8.03 (d, 1H), 8.83
(s, 1H).
EXAMPLE 26
(8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 29)
##STR00130##
Step 26.1:
(8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00131##
The procedure used is the same as that of step 12.3.
150 mg (0.591 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 99 .mu.l (0.709
mmol) of 1-bromopinacolone and 10 mL of acetonitrile were used in
the reaction. After purification by chromatography on silica gel
(eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 12 min 4% B, t
15 min 4% B, t 30 min 10% B), 188 mg of
(8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 352 tr (min)=2.38
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.17 (s, 9H),
2.20 (m, 1H), 2.45 (m, 1H), 3.25 (m, 2H), 4.35 (d, 1H), 4.63 (m,
1H), 5.05 (d, 1H), 5.92 (s, 1H).
Step 26.2:
(8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one
##STR00132##
The procedure used is the same as that of step 12.4.
180 mg (0.511 mmol) of
(8S)-2-chloro-9-(3,3-dimethyl-2-oxobutyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one, 76.32 mg (0.563 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 179
.mu.l (1.28 mmol) of triethylamine were used in the reaction. After
purification by chromatography on silica gel (eluent A/B: DCM/MeOH,
gradient A/B: t 0 min 0% B, t 15 min 4% B, t 18 min 4% B, t 33 min
10% B), 130 mg of
(8S)-9-(3,3-dimethyl-2-oxobutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
were obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 415 tr (min)=0.67
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.15 (s, 9H),
1.80 (m, 2H), 2.22 (m, 1H), 2.37 (m, 1H), 3.13 (m, 1H), 3.25 (m,
2H), 3.52 (m, 1H), 3.65 (m, 1H), 4.25 (d, 1H), 4.34 (m, 2H), 4.58
(m, 1H), 4.67 (m, 2H), 5.32 (d, 1H).
EXAMPLE 27
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-yleth-
yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 2)
##STR00133##
Step 27.1:
(8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00134##
The procedure used is the same as that of step 12.3.
1 g (3.94 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, 3.85 g (11.83 mmol) of cesium carbonate, 1.33 g (4.73
mmol) of 2-bromo-1-pyrid-4-ylethanone hydrobromide and 100 mL of
acetonitrile were used in the reaction. After purification by
chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient
A/B: t 0 min 60% B, t 25 min 100% B, t 30 min 100% B), 804 mg of
(8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 373 tr (min)=1.77
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.28 (m, 1H),
3.36 (m, 2H), 4.40 (m, 1H), 4.73 (m, 1H), 4.98 (d, 1H), 5.54 (d,
1H), 5.95 (s, 1H), 7.92 (m, 2H), 8.87 (m, 2H).
Step 27.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-py-
rid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one
##STR00135##
The procedure used is the same as that of step 12.4.
250 mg (0.67 mmol) of
(8S)-2-chloro-9-(2-oxo-2-pyrid-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one, 109 mg (0.80 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 230
.mu.l (1.68 mmol) of triethylamine were used in the reaction. After
purification by chromatography on silica gel (eluent A/B: DCM/MeOH,
gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10%) 230 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-4-ylet-
hyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
were obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min)=0.50
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (m, 1H),
1.72 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 3.00 (m, 1H), 3.10 (m,
1H), 3.20 (m, 1H), 3.30 (m, 2H), 4.38 (m, 1H), 4.42 (m, 1H), 4.48
(m, 1H), 4.62 (m, 1H), 4.37 (m, 1H), 4.75 (d, 1H), 5.58 (d, 1H),
7.88 (m, 2H), 8.85 (m, 2H).
EXAMPLE 28
(8S)-9-[2-(6-methyl
pyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-tr-
ifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 4)
##STR00136##
Step 28.1: 2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide
##STR00137##
The procedure used is the same as that of step 12.2.
500 mg (3.59 mmol) of 1-(6-methylpyrid-3-yl)ethanone, 590 .mu.l
(3.59 mmol) of hydrobromic acid, 204 .mu.l (3.95 mmol) of bromine
and 10 mL of glacial acetic acid were used in the reaction. After
precipitation with ethyl ether and filtration, 1.02 g of
2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide are obtained,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 214 tr (min)=1.00
Step 28.2:
(8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoro-
methyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00138##
1 g (3.94 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one is added to a suspension of 394.27 mg (9.86 mmol) of sodium
hydride in 40 mL of DMF. The reaction mixture is placed under
magnetic stirring at room temperature for 15 minutes. A solution of
1.16 g (3.94 mmol) of 2-bromo-1-(6-methylpyrid-3-yl)ethanone
hydrobromide in 10 mL of DMF is added dropwise to the reaction
medium at 0.degree. C. The reaction is stirred at room temperature
overnight. The reaction medium is evaporated to dryness. The crude
product is taken up in water and extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. After purification by chromatography on silica gel (eluent
A/B: heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t
40 min 60% B), 480 mg of
(8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one were obtained,
corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min)=1.85
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.30 (m, 1H),
2.58 (s, 3H), 3.29 (m, 2H), 4.40 (m, 1H), 4.75 (m, 1H), 4.93 (d,
1H), 5.55 (d, 1H), 5.94 (s, 1H), 7.46 (m, 1H), 8.26 (m, 1H), 9.09
(m, 1H).
Step 28.3: (8S)-9-[2-(6-methyl
pyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-tr-
ifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00139##
The procedure used is the same as that of step 12.4.
480 mg (1.24 mmol) of
(8S)-2-chloro-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 201.94 mg (1.49
mmol) of (1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and
313.97 mg (3.10 mmol) of triethylamine were used in the reaction.
After purification by chromatography on silica gel (eluent A/B:
heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40
min 60% B), 335 mg of
(8S)-9-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.49
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (m, 2H),
2.30 (m, 1H), 2.42 (m, 1H), 2.55 (s, 3H), 2.70-3.10 (bs, 3H), 3.20
(m, 2H), 4.40 (m, 3H), 4.65 (m, 3H), 5.70 (m, 1H), 7.49 (m, 1H),
8.30 (m, 1H), 9.10 (m, 1H).
EXAMPLE 29
2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicycl-
o[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one (Compound 17)
##STR00140##
Step 29.1:
(S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-t-
rifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
##STR00141##
500 mg (1.97 mmol) of
(S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyri-
midin-5-one are added to a suspension of 141.94 mg (5.91 mmol) of
sodium hydride in 20 mL of DMF. The reaction mixture is placed
under magnetic stirring at room temperature for 15 minutes. A
solution of 872.32 mg (2.96 mmol) of
2-bromo-1-(6-methylpyrid-3-yl)ethanone hydrobromide in 10 mL of DMF
is added dropwise to the reaction medium at 0.degree. C. The
reaction is stirred at room temperature overnight. The reaction
medium is evaporated to dryness. The crude product is taken up in
water and extracted with ethyl acetate. The organic phase is dried
over magnesium sulfate and evaporated to dryness. After
purification by chromatography on silica gel (eluent A/B:
heptane/EtOAc, gradient A/B: t 0 min 30% B, t 35 min 60% B, t 40
min 60% B), 150 mg of
(S)-7-chloro-2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-2-trifluorome-
thyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained,
corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 387 tr (min)=1.79
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.54 (s, 3H),
2.46 (s, 3H), 4.10 (d, 1H), 4.27 (d, 1H), 4.88 (d, 1H), 5.20 (d,
1H), 5.83 (s, 1H), 7.36 (m, 1H), 7.8.17 (m, 1H), 9.00 (m, 1H).
Step 29.2: 2-methyl-1-[2-(6-methyl
pyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((-
S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
##STR00142##
The procedure used is the same as that of step 12.4.
150 mg (0.388 mmol) of (S)-7-chloro-2-methyl-1-[2-(6-methyl
pyrid-3-yl)-2-oxoethyl]-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one, 63.11 mg (0.465 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 98.61 mg
(0.970 mmol) of triethylamine were used in the reaction. After
purification by chromatography on silica gel (eluent A/B: DCM/MeOH,
gradient A/B: t 0 min 0% B, t 35 min 10% B, t 40 min 10% B), 65 mg
of
2-methyl-1-[2-(6-methylpyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]py-
rimidin-5-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 450 tr (min)=0.49
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (s, 3H),
1.67-1.76 (bs, 2H), 2.96-3.24 (bs, 2H), 3.28 (m, 2H), 2.58 (s, 3H),
4.02 (d, 1H), 4.24 (d, 1H), 4.48 (m, 3H), 4.85 (d, 1H), 5.20 (d,
1H), 7.49 (m, 1H), 8.30 (m, 1H), 9.10 (m, 1H).
EXAMPLE 30
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3-y-
lethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-o-
ne (Compound 21)
##STR00143##
150 mg (0.474 mmol) of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one are added to a
suspension of 47.42 mg (1.19 mmol) of sodium hydride in 10 mL of
DMF. The reaction mixture is placed under magnetic stirring at room
temperature for 15 minutes. A solution of 168.31 mg (0.569 mmol) of
2-bromo-1-pyrid-3-ylethanone hydrobromide in 5 mL of DMF is added
dropwise to the reaction medium at 0.degree. C. The reaction is
stirred at room temperature overnight. The reaction medium is
evaporated to dryness. The crude product is taken up in water and
extracted with ethyl acetate. The organic phase is dried over
magnesium sulfate and evaporated to dryness. After purification by
chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t
0 min 0% B, t 35 min 10% B, t 40 min 10% B), 58 mg of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-1-(2-oxo-2-pyrid-3--
ylethyl)-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5--
one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min)=0.51
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.58 (s, 3H),
1.62 (m, 2H), 2.80-3.25 (bs, 5H) 3.95 (d, 1H), 4.15 (d, 1H), 4.50
(m, 2H), 4.80 (d, 1H), 5.15 (d, 1H), 7.51 (m, 1H), 8.30 (m, 1H),
8.78 (m, 1H), 9.20 (m, 1H).
EXAMPLE 31
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 12)
##STR00144##
Step 31.1: 2-pyrid-3-ylethyl toluene-4-sulfonate
##STR00145##
6.62 mL (47.26 mmol) of triethylamine and 8.26 g (43.32 mmol) of
4-methylbenzenesulfonyl chloride are added at 0.degree. C. to a
solution of 5 g (39.38 mmol) of 2-pyrid-3-ylethanol in 300 mL of
dichloromethane. After allowing the reaction medium to warm to room
temperature and stirring overnight, it is washed with water and
with saturated NaCl solution. The organic phase is dried over
magnesium sulfate and evaporated to dryness. After purification by
chromatography on silica gel (eluent: 4/6 heptane/EtOAc), 8 g of
2-pyrid-3-ylethyl toluene-4-sulfonate were obtained, corresponding
to the following characteristics:
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.41 (s, 3H),
2.91 (m, 2H), 4.27 (m, 2H), 7.27 (m, 1H), 7.43 (m, 2H), 7.56 (m,
1H), 7.68 (m, 2H), 8.40 (m, 2H).
Step 31.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3--
ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e
##STR00146##
A suspension of 150 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 170.15 mg (0.522
mmol) of cesium carbonate in 10 mL of acetonitrile is stirred for
15 minutes at 85.degree. C. 131.53 mg (0.474 mmol) of
2-pyrid-3-ylethyl toluene-4-sulfonate are then added. After
stirring overnight at 85.degree. C., the reaction mixture is
evaporated and the residue is taken up in water and extracted with
ethyl acetate. The organic phase is dried over magnesium sulfate
and evaporated to dryness. After purification by chromatography on
silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 35
min 10% B, t 40 min 10% B) 145 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-pyrid-3-ylethyl)-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
were obtained, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 422 tr (min)=0.39
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.25 (m, 2H),
1.85 (m, 2H), 2.01 (m, 1H), 2.35 (m, 1H), 2.95 (m, 3H), 3.15 (m,
1H), 3.42 (m, 1H), 3.75 (m, 2H), 4.22 (m, 2H), 4.72 (m, 3H), 7.35
(m, 1H), 7.65 (m, 1H), 8.45 (m, 2H).
EXAMPLE 32
(8S)-9-[2-(6-methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one (Compound 45)
##STR00147##
Step 32.1: 1-(6-methoxypyrid-3-yl)ethanone
##STR00148##
A mixture of 15 mL of methanol, 500 mg (2.89 mmol) of
1-(6-chloropyrid-3-yl)ethanone and 1.17 g (21.69 mmol) of sodium
methoxide is heated in a microwave reactor at 160.degree. C. for 4
hours. The reaction medium is evaporated to dryness. After
purification by chromatography on silica gel (eluent A/B:
heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 20% B, t 30 min
40% B), 230 mg of 1-(6-methoxypyrid-3-yl)ethanone were obtained,
corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 152 tr (min)=1.33
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.50 (s, 3H),
3.94 (s, 3H), 6.92 (m, 1H), 8.18 (m, 1H), 8.83 (m, 1H).
Step 32.2: 2-bromo-1-(6-methoxypyrid-3-yl)ethanone hydrobromide
##STR00149##
The procedure used is the same as that of step 12.2.
230 mg (1.52 mmol) of 1-(6-methoxypyrid-3-yl)ethanone, 413 .mu.l
(7.61 mmol) of hydrobromic acid, 87 .mu.l (1.67 mmol) of bromine
and 5 mL of glacial acetic acid were used in the reaction. After
precipitation with ethyl ether and filtration, 430 mg of
2-bromo-1-(6-methoxypyrid-3-yl)ethanone hydrobromide are obtained,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 230 tr (min)=1.61
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 3.96 (s, 3H),
4.91 (s, 2H), 6.96 (m, 1H), 8.21 (m, 1H), 8.88 (m, 1H).
Step 32.3:
(8S)-9-[2-(6-methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-a-
zabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-
-a]pyrimidin-4-one
##STR00150##
The procedure used is the same as that of step 12.3.
150 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 464.04 mg (1.42 mmol)
of cesium carbonate, 176.98 mg (0.569 mmol) of
2-bromo-1-(6-methoxypyrid-3-yl)ethanone hydrobromide and 10 mL of
acetonitrile were used in the reaction. After purification by
chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t
0 min 0% B, t 25 min 10% B, t 30 min 10% B), 100 mg of
(8S)-9-[2-(6-methoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[-
2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimid-
in-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 466 tr (min)=0.61
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62 (m, 1H),
1.71 (m, 1H), 2.25 (m, 1H), 2.41 (m, 1H), 2.61-3.17 (bs, 3H), 3.25
(m, 2H), 3.95 (s, 3H), 3.38 (m, 1H), 4.48 (m, 2H), 4.62 (m, 3H),
5.70 (m, 1H), 6.97 (m, 1H), 8.28 (m, 1H), 8.98 (s, 1H).
EXAMPLE 33
(S)-9-{2-[6-(2-fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]-
pyrimidin-4-one (Compound 63)
##STR00151##
Step 33.1: 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone
##STR00152##
530 .mu.l (8.68 mmol) of 2-fluoroethanol are added to a suspension
of 347.05 mg (8.68 mmol) of sodium hydride in 10 mL of DMF. The
reaction mixture is placed under magnetic stirring at room
temperature for 15 minutes. A solution of 500 mg (2.89 mmol) of
1-(6-chloropyrid-3-yl)ethanone in 3 mL of DMF is added dropwise to
the reaction medium. The reaction is stirred at room temperature
overnight. The reaction medium is evaporated to dryness. The crude
product is taken up in water and extracted with ethyl acetate. The
organic phase is dried over magnesium sulfate and evaporated to
dryness. After purification by chromatography on silica gel (eluent
A/B: heptane/EtOAc, gradient A/B: t 0 min 0% B, t 5 min 10% B, t 30
min 30% B), 362 mg of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone were
obtained, corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 184 tr (min)=1.41
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.57 (s, 3H),
4.56 (m, 1H), 4.67 (m, 1H), 4.86 (m, 1H), 7.00 (m, 1H), 8.21 (m,
1H), 8.83 (m, 1H).
Step 33.2: 2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone
hydrobromide
##STR00153##
The procedure used is the same as that of step 12.2.
362 mg (1.98 mmol) of 1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone, 413
.mu.l (7.61 mmol) of hydrobromic acid, 537 .mu.l (9.88 mmol) of
bromine and 5 mL of glacial acetic acid were used in the reaction.
After precipitation with ethyl ether and filtration, 602 mg of
2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone hydrobromide are
obtained, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 264 tr (min)=1.69
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 4.56
(m, 1H), 4.69 (m, 1H), 4.86 (m, 1H), 4.92 (s, 2H), 7.00 (m, 1H),
8.23 (m, 1H), 8.85 (m, 1H), 9.80 (bs, 1H).
Step 33.3:
(8S)-9-{2-[6-(2-fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)--
2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyr-
imido[1,2-a]pyrimidin-4-one
##STR00154##
The procedure used is the same as that of step 12.3.
150 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 464.04 mg (1.42 mmol)
of cesium carbonate, 195.20 mg (0.569 mmol) of
2-bromo-1-[6-(2-fluoroethoxy)pyrid-3-yl]ethanone hydrobromide and
10 mL of acetonitrile were used in the reaction. After purification
by chromatography on silica gel (eluent A/B: DCM/MeOH, gradient
A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 10% B), 130 mg of
(8S)-9-{2-[6-(2-fluoroethoxy)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H].sup.+: m/z 498 tr (min)=0.62
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62 (m, 1H),
1.72 (m, 1H), 2.25 (m, 1H), 2.45 (m, 1H), 2.61-3.17 (bs, 3H), 2.25
(m, 2H), 4.38 (m, 1H), 4.50 (m, 2H), 4.55-4.70 (m, 5H), 4.74 (m,
1H), 4.83 (m, 1H), 5.70 (m, 1H), 7.12 (m, 1H), 8.30 (m, 1H), 8.97
(m, 1H).
EXAMPLE 34
(8S)-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabic-
yclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one (Compound 71)
##STR00155##
200 mg (0.61 mmol) of
(8S)-2-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetr-
ahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF are added to a
suspension of 60 mg (1.51 mmol) of sodium hydride in 10 mL of DMF.
The reaction mixture is heated at 50.degree. C. for 10 minutes.
After addition of 162 mg (0.79 mmol) of
(S)-2-chloro-1-(4-fluoro-2-methoxyphenyl)ethanol, the reaction is
continued at room temperature overnight. The reaction medium is
evaporated to dryness. The residue is purified by chromatography on
a column of silica (eluent: 90/10 DCM/MeOH). 40 mg of
(8S)-9-[(S)-2-(4-fluoro-2-methoxyphenyl)-2-hydroxyethyl]-2-(8-oxa-3-azabi-
cyclo[3.2.1]oct-3-yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method B): ESI+ [M+H]+: m/z 499 tr (min)=0.71
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (m, 2H),
1.83 (m, 2H), 2.25 (m, 1H), 2.35 (m, 1H), 2.92 (m, 3H), 3.22 (m,
1H), 3.75 (m, 1H), 3.75 (s, 3H), 3.85 (m, 1H), 4.15 (m, 1H), 4.35
(m, 3H), 4.71 (m, 1H), 4.89 (s, 1H), 5.35 (m, 1H), 5.53 (m, 1H),
6.78 (m, 1H), 6.87 (m, 1H), 7.51 (m, 1H).
EXAMPLE 35
(S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct--
3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
(Compound 72)
##STR00156##
Step 35.1:
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluor-
omethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
##STR00157##
A mixture of 40 mL of DMF, 2 g (7.89 mmol) of
(S)-7-chloro-2-methyl-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyri-
midin-5-one, 3.44 g (11.84 mmol) of
1-benzyloxy-4-(2-bromoethyl)benzene and 5.14 g (15.78 mmol) of
cesium carbonate is heated in a Biotage microwave reactor at
120.degree. C. for 20 minutes. The reaction medium is evaporated to
dryness. After purification by chromatography on silica gel (eluent
A/B: heptane/EtOAc, gradient A/B: t 0 min 20% B, t 25 min 50% B, t
35 min 50% B), 2.8 g of
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,-
3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one were obtained,
corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 464 tr (min)=2.91
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.36 (s, 3H),
2.90 (m, 1H), 3.11 (m, 1H), 3.49 (m, 1H), 3.75 (m, 1H), 4.38 (d,
1H), 5.07 (m, 2H), 5.32 (s, 1H), 5.97 (s, 1H), 6.94 (m, 2H), 7.12
(m, 2H), 7.43 (m, 5H).
Step 35.2:
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyc-
lo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidi-
n-5-one
##STR00158##
The procedure used is the same as that of step 12.4.
1.40 g (3.02 mmol) of
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-7-chloro-2-methyl-2-trifluoromethyl-2,-
3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one, 903 mg (6.04 mmol) of
8-oxa-3-azabicyclo[3.2.1]octane hydrochloride and 763 mg (7.54
mmol) of triethylamine were used in the reaction. After
purification by chromatography on silica gel (eluent A/B: 2/8
heptane/EtOAc), 1.2 g of
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
were obtained, corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 541 tr (min)=2.84
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.49 (s, 3H),
1.66 (m, 2H), 1.83 (m, 2H), 2.79 (m, 1H), 2.96 (m, 3H), 3.45 (m,
2H), 3.86 (m, 3H), 4.10 (d, 1H), 4.39 (m, 2H), 4.78 (m, 1H), 5.08
(s, 2H), 6.96 (m, 2H), 7.15 (m, 2H), 7.41 (m, 5H).
Step 35.3:
(S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo-
[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin--
5-one
##STR00159##
700 mg (11.10 mmol) of ammonium formate and 156 mg (0.22 mmol) of
20% palladium hydroxide are added at 0.degree. C. to a solution of
1.20 g (2.22 mmol) of
(S)-1-[2-(4-benzyloxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]o-
ct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
in 15 mL of methanol. The mixture is refluxed for 1 hour and then
allowed to cool to room temperature. The reaction medium is
filtered through Celite and the filtrate is then evaporated to
dryness. After purification by chromatography on silica gel (eluent
A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min
10% B), 732 mg of
(S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-
-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
were obtained, corresponding to the following characteristics:
LC/MS (method B): ESI+ [M+H]+: m/z 451 tr (min)=0.68
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.48 (s, 3H),
1.64 (m, 2H), 1.80 (m, 2H), 2.72 (m, 1H), 2.87 (m, 1H), 3.00 (m,
2H), 3.35 (m, 1H), 3.52 (m, 1H), 3.78 (m, 3H), 4.09 (d, 1H), 4.39
(m, 2H), 4.77 (s, 1H), 6.68 (m, 2H), 6.97 (m, 2H), 9.16 (s,
1H).
EXAMPLE 36
(S)-1-{2-[4-(2-dimethylaminoethoxy)phenyl]ethyl}-2-methyl-7-(8-oxa-3-azabi-
cyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrim-
idin-5-one (Compound 74)
##STR00160##
282 mg (0.87 mmol) of cesium carbonate are added to a solution of
130 mg (0.29 mmol) of
(S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-
-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
in 10 mL of DMF. After heating at 80.degree. C. for 20 minutes,
62.40 mg (0.43 mmol) of (2-chloroethyl)dimethylamine are added. The
reaction medium is heated at 80.degree. C. overnight. The reaction
medium is evaporated to dryness. After purification by
chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t
0 min 0% B, t 25 min 10% B, t 30 min 10% B), 116 mg of
(S)-1-{2-[4-(2-dimethylaminoethoxyl)phenyl]ethyl}-2-methyl-7-(8-oxa-3-aza-
bicyclo[3.2.1]oct-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyr-
imidin-5-one were obtained, corresponding to the following
characteristics:
LC/MS (method B): ESI+ [M+H]+: m/z 522 tr (min)=0.56
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.48 (s, 3H),
1.62 (m, 2H), 1.77 (m, 2H), 2.77 (m, 7H), 2.88 (m, 1H), 2.93 (m,
2H), 3.40 (m, 4H), 3.57-378 (bs, 2H), 3.82 (m, 1H), 4.06 (m, 1H),
4.26 (m, 2H), 4.33 (m, 2H), 4.72 (s, 1H), 6.90 (m, 2H), 7.12 (m,
2H), 10.2 (bs, 1H).
EXAMPLE 37
N,
N-dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)--
5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}-
phenoxy)acetamide (Compound 70)
##STR00161##
235 mg (0.72 mmol) of cesium carbonate are added to a solution of
130 mg (0.29 mmol) of
(S)-1-[2-(4-hydroxyphenyl)ethyl]-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-
-3-yl)-2-trifluoromethyl-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one
in 10 mL of DMF. After heating at 80.degree. C. for 20 minutes,
52.60 mg (0.43 mmol) of 2-chloro-N,N-dimethylacetamide and 43.30 mg
(0.29 mmol) of sodium iodide are added. The reaction medium is
heated at 80.degree. C. overnight. The reaction medium is
evaporated to dryness. After purification by chromatography on
silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25
min 10% B, t 30 min 10% B), 138 mg of
N,N-dimethyl-2-(4-{2-[(S)-2-methyl-7-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)--
5-oxo-2-trifluoromethyl-2,3-dihydro-5H-imidazo[1,2-a]pyrimidin-1-yl]ethyl}-
phenoxy)acetamide were obtained, corresponding to the following
characteristics:
LC/MS (method B): ESI+ [M+H]+: m/z 536 tr (min)=0.69
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.53 (s, 3H),
1.68 (m, 2H), 1.82 (m, 2H), 2.75 (m, 1H), 2.81 (s, 3H), 2.95 (m,
3H), 2.97 (s, 3H), 3.38 (m, 1H), 3.52 (m, 1H), 3.73 (m, 2H), 3.82
(d, 1H), 4.13 (d, 1H), 4.41 (m, 2H), 4.74 (s, 2H), 4.76 (s, 1H),
6.85 (m, 2H), 7.12 (m, 2H).
EXAMPLE 38
(8S)-9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5--
yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 54)
##STR00162##
Step 38.1: methyl
((8S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.]hept-5-yl-6-oxo-2-trifluoromethyl-
-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate
##STR00163##
150 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are
added to a suspension of 18.97 mg (0.474 mmol) of sodium hydride in
7 mL of DMF. The reaction mixture is stirred at room temperature
for 10 minutes. After addition of 45 .mu.l (0.474 mmol) of methyl
bromoacetate, the reaction is stirred at room temperature
overnight. The reaction medium is evaporated to dryness. The
residue is purified by chromatography on a column of silica
(eluent: 95/5 DCM/MeOH). 147 mg of methyl
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethy-
l-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate were
obtained, corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 389 tr (min)=1.70
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.81 (m, 2H),
2.11 (m, 1H), 2.40 (m, 1H), 3.13 (m, 3H), 3.50 (m, 1H), 3.57 (s,
3H), 3.69 (m, 1H), 4.16 (m, 1H), 4.27 (m, 1H), 4.50 (m, 1H), 4.68
(m, 4H).
Step 38.2:
(8S)-9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.-
2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-
-4-one
##STR00164##
631 .mu.l (1.89 mmol) of a 3 M solution of ethylmagnesium bromide
in ethyl ether are added at 0.degree. C. to a solution of 147 mg
(0.38 mmol) of methyl
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trif-
luoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate
in 10 mL of THF. The reaction medium is stirred at 0.degree. C. for
4 hours, followed by addition of 10 mL of saturated ammonium
chloride solution. The resulting mixture is extracted with ethyl
acetate and the organic phase is then dried over magnesium sulfate
and evaporated to dryness. After purification by chromatography on
silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25
min 10% B, t 30 min 10% B), 80 mg of
(8S)-9-(2-ethyl-2-hydroxybutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
were obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 417 tr (min)=0.63
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.76 (m, 3H),
0.83 (m, 3H), 1.30 (m, 1H), 1.36 (m, 1H), 1.42 (m, 2H), 1.83 (m,
2H), 2.25 (m, 1H), 2.39 (m, 1H), 2.99 (m, 1H), 3.24 (m, 1H), 3.30
(m, 2H), 3.57 (m, 1H), 3.70 (m, 1H), 4.13 (m, 1H), 4.61 (m, 3H),
4.72 (m, 1H), 4.98 (m, 1H).
EXAMPLE 39
(8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 49)
##STR00165##
Step 39.1: methyl
3-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromet-
hyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate
##STR00166##
1 .mu.l (0.006 mmol) of DBU and 274.94 mg (3.16 mmol) of methyl
acrylate are added to a solution of 200 mg (0.632 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 5 mL of DMF. The
reaction mixture is stirred at room temperature overnight. The
reaction medium is evaporated to dryness. The residue is purified
by chromatography on a column of silica (eluent: 95/5 DCM/MeOH).
245 mg of methyl
3-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromet-
hyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate
were obtained, corresponding to the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 403 tr (min)=1.83
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.61 (m, 2H),
1.85 (m, 1H), 2.11 (m, 1H), 2.43 (m, 1H), 2.61 (m, 1H), 2.88 (m,
2H), 3.09 (m, 2H), 3.35 (m, 4H), 3.48 (m, 1H), 3.95 (m, 2H), 4.45
(m, 4H).
Step 39.2:
(8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one
##STR00167##
911 .mu.l (2.73 mmol) of a 3 M solution of ethylmagnesium bromide
in ethyl ether are added at 0.degree. C. to a solution of 220 mg
(0.55 mmol) of methyl
3-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-tr-
ifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate
in 10 mL of THF. The reaction medium is stirred at 0.degree. C. for
2 hours. 10 mL of saturated ammonium chloride solution are added to
the reaction medium. The resulting mixture is extracted with ethyl
acetate and the organic phase is then dried over magnesium sulfate
and evaporated to dryness. After purification by chromatography on
silica gel (eluent A/B: DCM/MeOH, gradient A/B: t 0 min 0% B, t 25
min 10% B, t 30 min 10% B), 128 mg of
(8S)-9-(3-ethyl-3-hydroxypentyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
were obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 431 tr (min)=0.63
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.80 (m, 6H),
1.36 (m, 4H), 1.63 (m, 1H), 1.71 (m, 1H), 1.82 (m, 2H), 2.05 (m,
1H), 2.34 (m, 1H), 3.15 (m, 1H), 3.23 (m, 1H), 3.62 (m, 1H), 3.70
(m, 1H), 3.99 (m, 1H), 4.19 (m, 2H), 4.51 (m, 2H), 4.64 (m, 2H),
5.01-5.12 (bs, 1H).
EXAMPLE 40
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-pyrid-2-yleth-
yl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 68)
##STR00168##
Step 40.1:
(8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7-
,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00169##
The procedure used is the same as that of step 12.3.
150 mg (0.591 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one, 578.71 mg (1.77 mmol) of cesium carbonate, 199.40 mg
(0.709 mmol) of 2-bromo-1-pyrid-2-ylethanone hydrobromide and 10 mL
of acetonitrile were used in the reaction. After purification by
chromatography on silica gel (eluent A/B: heptane/EtOAc, gradient
A/B: t 0 min 0% B, t 15 min 50% B, t 25 min 70% B), 218 mg of
(8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one were obtained, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 373 tr (min)=2.14
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.28 (m, 1H),
3.40 (m, 1H), 4.40 (m, 1H), 4.80 (m, 1H), 5.11 (d, 1H), 5.61 (d,
1H), 5.77 (m, 1H), 5.93 (s, 1H), 7.76 (m, 1H), 8.00 (m, 1H), 8.08
(m, 1H), 8.79 (m, 1H).
Step 40.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-py-
rid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one
##STR00170##
The procedure used is the same as that of step 12.4.
218 mg (0.58 mmol) of
(8S)-2-chloro-9-(2-oxo-2-pyrid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetra-
hydropyrimido[1,2-a]pyrimidin-4-one, 95.17 mg (0.702 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride and 205
.mu.l (1.46 mmol) of triethylamine were used in the reaction. After
purification by chromatography on silica gel (eluent A/B: 95/5
DCM/MeOH), 103 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-oxo-2-py-
rid-2-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 436 tr (min)=0.59
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.59 (m, 1H),
1.68 (m, 1H), 2.24 (m, 1H), 2.44 (m, 1H), 2.90 (m, 2H), 3.08-3.20
(bs, 2H), 3.25 (m, 1H), 4.26 (m, 1H), 4.37 (m, 1H), 4.47 (m, 1H),
4.62 (m, 1H), 4.72 (m, 1H), 4.82 (m, 1H), 5.70 (m, 1H), 7.73 (m,
1H), 7.98 (m, 1H), 8.07 (m, 1H), 8.78 (m, 1H).
EXAMPLE 41
(8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,4S)-2-oxa--
5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one (Compound 14)
##STR00171##
Step 41.1:
(8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-az-
abicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2--
a]pyrimidin-4-one
##STR00172##
100 mg (0.32 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are
added to a suspension of 41.73 mg (1.04 mmol) of sodium hydride in
5 mL of DMF. The reaction mixture is stirred at room temperature
for 10 minutes. After addition of 244.65 mg (1.04 mmol) of
2-bromo-1-(6-chloropyrid-3-yl)ethanone, the reaction is continued
at room temperature overnight. The reaction medium is evaporated to
dryness. The residue is purified by chromatography on a column of
silica (eluent: 90/10 DCM/MeOH). 85 mg of
(8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 470 tr (min)=1.86
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.65 (m, 2H),
2.28 (m, 1H), 2.93 (m, 3H), 3.19 (m, 3H), 4.45 (m, 3H), 4.71 (m,
3H), 5.74 (m, 1H), 7.78 (m, 1H), 8.41 (m, 1H), 9.10 (m, 1H).
Step 41.2:
(8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S-
,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahyd-
ropyrimido[1,2-a]pyrimidin-4-one
##STR00173##
A mixture of 0.50 mL of ethanol, 33 mg (0.070 mmol) of
(8S)-9-[2-(6-chloropyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyclo[2-
.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 21.41 .mu.l (0.352 mmol) of ethanolamine is heated in a
Biotage microwave reactor at 130.degree. C. for 30 minutes. The
reaction mixture is evaporated to dryness and the residue is then
taken up in 10 mL of water. The precipitate is filtered off and
then dried under vacuum. 17 mg of
(8S)-9-{2-[6-(2-hydroxyethylamino)pyrid-3-yl]-2-oxoethyl}-2-(1S,-
4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydr-
opyrimido[1,2-a]pyrimidin-4-one are obtained, the characteristics
of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 495 tr (min)=0.40
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62 (m, 1H),
1.73 (m, 1H), 2.23 (m, 1H), 2.41 (m, 1H), 2.91-3.12 (bs, 3H), 3.23
(m, 1H), 3.42 (m, 2H), 3.54 (m, 2H), 4.36 (m, 2H), 4.49 (m, 2H),
4.60 (m, 2H), 4.74 (m, 1H), 5.60 (d, 1H), 6.58 (d, 1H), 7.53 (m,
1H), 7.88 (m, 1H), 8.77 (m, 1H).
EXAMPLE 42
(8S)-9-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicyc-
lo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyri-
midin-4-one (Compound 5)
##STR00174##
Step 42.1: 1-(6-methylaminopyrid-3-yl)ethanone
##STR00175##
A mixture of 2 mL of ethanol, 280 mg (1.80 mmol) of
1-(6-chloropyrid-3-yl)ethanone and 4.50 mL (9 mmol) of a 2 M
solution of methylamine in THF is heated in a Biotage microwave
reactor at 130.degree. C. for 30 minutes. The reaction medium is
evaporated to dryness. The crude product is taken up in water and
extracted with EtOAc. The organic phase is dried over magnesium
sulfate and evaporated to dryness. 258 mg of
1-(6-methylaminopyrid-3-yl)ethanone are obtained, the
characteristics of which are as follows:
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.42 (s, 3H),
2.84 (s, 3H), 6.47 (m, 1H), 7.42 (m, 1H), 7.85 (m, 1H), 8.65 (m,
1H).
Step 42.2: 2-bromo-1-(6-methylaminopyrid-3-yl)ethanone
##STR00176##
The procedure used is the same as that of step 12.2.
380 mg (2.53 mmol) of 1-(6-methylaminopyrid-3-yl)ethanone, 416
.mu.l (2.53 mmol) of hydrobromic acid, 130 .mu.l (2.53 mmol) of
bromine and 5 mL of glacial acetic acid were used in the reaction.
After precipitation with ethyl ether and filtration, the
precipitate is taken up in water. The solution is basified with
saturated NaHCO.sub.3 solution. The precipitate formed is filtered
off, washed with water and then dried under vacuum. 370 mg of
2-bromo-1-(6-methylaminopyrid-3-yl)ethanone are obtained, the
characteristics of which are as follows:
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 2.85
(s, 3H), 4.70 (s, 2H), 6.50 (m, 1H), 7.62 (m, 1H), 7.87 (m, 1H),
8.71 (m, 1H).
Step 42.3:
(8S)-9-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-
-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one
##STR00177##
100 mg (0.32 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in 3 mL of DMF are
added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride in
5 mL of DMF. The reaction mixture is stirred at room temperature
for 15 minutes. After dropwise addition of 79.67 mg (0.35 mmol) of
2-bromo-1-(6-methylaminopyrid-3-yl)ethanone dissolved in 3 mL of
DMF, the reaction is continued at room temperature for 1 hour. The
reaction medium is evaporated to dryness. The residue is purified
by chromatography on a column of silica (eluent A/B: DCM/MeOH,
gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 15% B). 75 mg
of
(8S)-9-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabicy-
clo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyr-
imidin-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 465 tr (min)=0.41
.sup.1H NMR spectrum (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.62
(m, 1H), 1.73 (m, 1H), 2.23 (m, 1H), 2.42 (m, 1H), 2.86 (s, 3H),
2.92-3.16 (bs, 3H), 3.23 (m, 2H), 4.37 (m, 2H), 4.49 (m, 2H), 4.60
(m, 2H), 5.60 (m, 1H), 6.51 (m, 1H), 7.47 (m, 1H), 7.92 (m, 1H),
8.78 (m, 1H).
EXAMPLE 43
2-methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-azab-
icyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2--
a]pyrimidin-5-one (Compound 9)
##STR00178##
100 mg (0.32 mmol) of
2-methyl-7-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromet-
hyl)-2,3-dihydro-1H-imidazo[1,2-a]pyrimidin-5-one in 3 mL of DMF
are added to a suspension of 13.91 mg (0.35 mmol) of sodium hydride
in 5 mL of DMF. The reaction mixture is stirred at room temperature
for 15 minutes. After dropwise addition of 79.67 mg (0.35 mmol) of
2-bromo-1-(6-methylaminopyrid-3-yl)ethanone dissolved in 3 mL of
DMF, the reaction is continued at room temperature for 1 hour. The
reaction medium is evaporated to dryness. The residue is purified
by chromatography on a column of silica (eluent A/B: DCM/MeOH,
gradient A/B: t 0 min 0% B, t 25 min 10% B, t 30 min 15% B). 100 mg
of
2-methyl-1-[2-(6-methylaminopyrid-3-yl)-2-oxoethyl]-7-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-2-((S)-trifluoromethyl)-2,3-dihydro-1H-imidazo[1,2-
-a]pyrimidin-5-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 465 tr (min)=0.42
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.61 (s, 3H),
1.70 (m, 1H), 1.75 (m, 1H), 2.86 (d, 3H), 2.93-3.26 (bs, 3H), 3.35
(m, 1H), 3.98 (m, 1H), 4.22 (m, 1H), 4.53 (m, 3H), 4.64 (d, 1H),
5.05 (d, 1H), 6.51 (m, 1H), 7.50 (m, 1H), 7.91 (m, 1H), 8.79 (m,
1H).
EXAMPLE 44
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorom-
ethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1-c-
arbaldehyde (Compound 90)
##STR00179##
Step 44.1: tert-butyl
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1--
carboxylate
##STR00180##
1.03 g (3.54 mmol) of tert-butyl
4-(2-bromoethyl)piperidine-1-carboxylate and 530 mg (3.54 mmol) of
sodium iodide are added to a solution of 800 mg (2.53 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 2.47 g (7.59 mmol)
of cesium carbonate in 15 mL of acetonitrile. The reaction mixture
is heated in a Biotage microwave reactor at 100.degree. C. for 1
hour 15 minutes. The reaction medium is evaporated to dryness and
the residue is taken up in EtOAc and washed with water and with
saturated NaCl. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 730
mg of tert-butyl
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1--
carboxylate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 528 tr (min)=2.57
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 0.98
(m, 2H), 1.24 (m, 1H), 1.38 (s, 9H), 1.47 (m, 1H), 1.61 (m, 3H),
1.84 (m, 2H), 2.03 (m, 1H), 2.33 (m, 1H), 2.68 (m, 2H), 3.13 (m,
3H), 3.32 (m, 3H), 3.57-3.75 (dd, 2H), 3.88 (m, 2H), 7.92 (m, 1H),
4.18 (m, 2H), 4.63 (m, 2H).
Step 44.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-piperidi-
n-4-ylethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin--
4-one
##STR00181##
A solution of 250 mg (0.473 mmol) of tert-butyl
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1--
carboxylate in 10 mL of formic acid is stirred for 1 hour 30
minutes at room temperature.
The reaction mixture is evaporated to dryness and the residue is
taken up in DCM and evaporated to give 224 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-piperid-4-ylethyl)-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 428 tr (min)=1.34
Step 44.3:
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-
-trifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]pip-
eridine-1-carbaldehyde
##STR00182##
33 mg (0.521 mmol) of ammonium formate are added to a suspension of
224 mg (0.474 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(2-piperid-4-ylethyl)-
-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
in 10 mL of 1,4-dioxane. The reaction mixture is heated at
100.degree. C. for 4 hours and then evaporated to dryness. The
residue is taken up in DCM and the solution is washed with water
and with saturated NaCl. The organic phase is dried over sodium
sulfate and evaporated to dryness. The product obtained is purified
by chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 85
mg of
4-[2-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoro-
methyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)ethyl]piperidine-1--
carbaldehyde, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 456 tr (min)=0.54
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.83-1.11 (m,
2H), 1.5 (m, 2H), 1.58-1.77 (m, 3H), 1.85 (m, 2H), 2.04 (m, 1H),
2.34 (m, 1H), 2.57 (m, 1H), 2.99 (m, 1H), 3.02-3.23 (m, 3H), 3.33
(m, 1H), 3.59-3.75 (m, 3H), 4.07-4.21 (m, 3H), 4.55-4.99 (m, 4H),
7.95 (s, 1H).
EXAMPLE 45
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahydropyran-4--
yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-o-
ne (Compound 92)
##STR00183##
Step 45.1: 2-(tetrahydro-2H-pyran-4-yl)ethyl
4-methylbenzenesulfonate
##STR00184##
629 .mu.L (4.47 mmol) of triethylamine and 813 mg (4.10 mmol) of
p-toluenesulfonyl chloride are added to a solution of 500 mg (3.73
mmol) of 2-(tetrahydropyran-4-yl)ethanol in 15 mL of DCM previously
cooled to 0.degree. C.
The reaction mixture is stirred at room temperature overnight. The
solution is taken up in DCM, washed with aqueous NaHCO.sub.3
solution, dried over magnesium sulfate and then evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 20/80 EtOAc/heptane) to give 840 mg of
2-(tetrahydro-2H-pyran-4-yl)ethyl 4-methylbenzenesulfonate,
corresponding to the following characteristics:
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.15-1.32 (m,
2H), 1.45-1.74 (m, 5H), 2.47 (s, 3H), 3.33 (td, 2H), 3.88-3.96 (m,
2H), 4.09 (t, 2H), 7.37 (d, 2H), 7.82 (d, 2H).
Step 45.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahy-
dropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one
##STR00185##
198 mg (0.698 mmol) of 2-(tetrahydro-2H-pyran-4-yl)ethyl
4-methylbenzenesulfonate and 104 mg (0.698 mmol) of sodium iodide
are added to a solution of 170 mg (0.537 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 525 mg (1.61 mmol)
of cesium carbonate in 5 mL of acetonitrile. The reaction mixture
is heated in a Biotage microwave reactor at 100.degree. C. for 1
hour 15 minutes. The reaction medium is evaporated to dryness and
the residue is taken up in EtOAc and washed with water and with
saturated NaCl. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 140 mg
of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(tetrahy-
dropyran-4-yl)ethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]py-
rimidin-4-one, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 429 tr (min)=0.61
.sup.1H NMR spectrum (600 MHz, .delta. in ppm, DMSO-d.sub.6):
1.09-1.25 (m, 2H), 1.46-1.57 (m, 3H), 1.58-1.67 (m, 2H), 1.82-1.89
(m, 2H), 2.04 (m, 1H), 2.34 (m, 1H), 2.96-2-3.22 (m, 3H), 3.23-3.37
(m, 4H), 3.63 (m, 1H), 3.73 (m, 1H), 3.82 (m, 2H), 4.11 (m, 1H),
4.21 (m, 1H), 4.57-5.01 (m, 3H).
EXAMPLE 46
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-ylm-
ethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 93)
##STR00186##
Step 46.1:
(8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl--
6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00187##
A suspension of 200 mg (0.788 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 771 mg (2.37 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 187 mg
(0.788 mmol) of (bromomethyl)tetrahydropyran are then added.
The reaction mixture is heated in a Biotage microwave reactor at
100.degree. C. for 50 minutes. The crude product is evaporated and
the residue is taken up in water and extracted with ethyl acetate.
The organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 95/5 DCM/MeOH) to give 220 mg of
(8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-te-
trahydropyrimido[1,2-a]pyrimidin-4-one, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 352 tr (min)=2.08
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6):
1.04-1.42 (m, 2H), 1.42-1.57 (m, 2H), 2.04-2.33 (m, 2H), 2.34-2.46
(m, 1H), 2.95-3.07 (m, 1H), 3.17-3.30 (m, 3H), 3.79-3.89 (m, 2H),
4.04-4.21 (m, 2H), 4.72 (m, 1H), 5.89 (s, 1H).
Step 46.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydro-
pyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrim-
idin-4-one
##STR00188## 220 mg (0.62 mmol) of
(8S)-2-chloro-9-(tetrahydropyran-4-ylmethyl)-8-trifluoromethyl-6,7,8,9-te-
trahydropyrimido[1,2-a]pyrimidin-4-one and 127 mg (0.93 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 244 .mu.L
(1.75 mmol) of triethylamine are added. The tube is sealed and
heated at 130.degree. C. in an oil bath for 4 hours. The crude
product obtained is taken up in ethyl acetate and the organic phase
is washed with water, dried over magnesium sulfate and then
evaporated to dryness. The residue is purified by chromatography on
silica gel (eluent: 95/5 DCM/MeOH) to give 180 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(tetrahydropyran-4-yl-
methyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one-
, the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 415 tr (min)=0.57
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.10-1.38 (m,
2H), 1.40-1.56 (m, 2H), 1.79-1.89 (m, 2H), 2.06-2.22 (m, 2H), 2.32
(m, 1H), 2.89 (m, 1H), 2.95-3.14 (m, 2H), 3.20 (m, 3H), 3.61 (m,
1H), 3.73 (m, 1H), 3.83 (m, 2H), 4.07-4.17 (m, 2H), 4.56 (m, 1H),
4.60-4.96 (m, 3H).
EXAMPLE 47
4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorometh-
yl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carb-
aldehyde (Compound 95)
##STR00189##
Step 47.1: tert-butyl 4-bromomethylpiperidine-1-carboxylate
##STR00190##
A solution of 1 g (4.41 mmol) of tert-butyl
4-hydroxymethylpiperidine-1-carboxylate in 25 mL of THF is cooled
to 0.degree. C. 1.34 g (5.07 mmol) of triphenylphosphine and 2.02 g
(5.96 mmol) of carbon tetrabromide are then added.
The reaction mixture is stirred at room temperature over the
weekend.
The solution is taken up in ethyl ether, the insoluble matter is
filtered off and the organic phase is evaporated to dryness. The
residue is purified by chromatography on silica gel (eluent: 80/20
EtOAc/heptane) to give 960 mg of tert-butyl
4-bromomethylpiperidine-1-carboxylate, the characteristics of which
are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 279 tr (min)=2.13
.sup.1H NMR (300 MHz, .delta. in ppm, CDCl.sub.3): 1.09-1.29 (m,
2H), 1.47 (s, 9H), 1.71-1.88 (m, 3H), 2.62-2.78 (m, 2H), 3.31 (d,
2H), 4.07-4.25 (m, 2H).
Step 47.2: tert-butyl
4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromet-
hyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-car-
boxylate
##STR00191## 788 mg (2.84 mmol) of tert-butyl
4-bromomethylpiperidine-1-carboxylate and 425 mg (2.84 mmol) of
sodium iodide are added to a solution of 690 mg (2.18 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 2.13 g (6.54 mmol)
of cesium carbonate in 10 mL of acetonitrile. The reaction mixture
is heated in a Biotage microwave reactor at 100.degree. C. for 3
hours. The reaction medium is evaporated to dryness and the residue
is taken up in EtOAc and washed with water and with saturated NaCl.
The organic phase is dried over magnesium sulfate and evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 95/5 DCM/MeOH) to give 510 mg of tert-butyl
4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromet-
hyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-car-
boxylate, the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 514 tr (min)=2.45
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 0.93-1.03 (m,
1H), 1.11-1.32 (m, 3H), 1.38 (s, 9H), 1.44-1.64 (m, 2H), 1.76-1.91
(m, 2H), 1.99-2.39 (m, 3H), 2.78-3.32 (m, 5H), 3.60 (m, 1H), 3.71
(m, 1H), 3.86-3.99 (m, 2H), 4.06-4.19 (m, 2H), 4.48-4.92 (m,
3H).
Step 47.3:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-y-
lmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00192##
A solution of 280 mg (0.545 mmol) of tert-butyl
4-((S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluorometh-
yl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-carb-
oxylate in 10 mL of formic acid is stirred for 2 hours at room
temperature. The reaction mixture is evaporated to dryness and the
residue is taken up in DCM and evaporated to give 250 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-ylmethyl-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method G): ESI+ [M+H]+: m/z 414 tr (min)=1.31
Step 47.4:
4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-tr-
ifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperi-
dine-1-carbaldehyde
##STR00193##
41 mL (0.817 mmol) of ammonium formate are added to a suspension of
250 mg (0.545 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-piperid-4-ylmethyl-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one in
10 mL of 1,4-dioxane. The reaction mixture is heated at 100.degree.
C. for 2 hours and then evaporated to dryness. The residue is taken
up in EtOAc and washed with aqueous NaHCO.sub.3 solution and with
saturated NaCl. The organic phase is dried over sodium sulfate and
evaporated to dryness. The product obtained is purified by
chromatography on silica gel (eluent: 90/10 DCM/MeOH) to give 120
mg of
4-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromet-
hyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-ylmethyl)piperidine-1-car-
baldehyde, the characteristics of which are as follows:
LC/MS (method D): ESI+ [M+H]+: m/z 442 tr (min)=0.82
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.91-1.24 (m,
2H), 1.56-1.75 (m, 2H), 1.81-1.91 (m, 2H), 2.14-2.29 (m, 2H), 2.36
(m, 1H), 2.54 (m, 1H), 2.96 (m, 2H), 3.15 (m, 1H), 3.21-3.40 (m,
2H), 3.66 (m, 2H), 3.74 (m, 1H), 4.10-4.23 (m, 3H), 4.51 (m, 1H),
4.58-4.84 (m, 3H), 7.99 (m, 1H).
EXAMPLE 48
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trifluoro-2-hyd-
roxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one (Compound 96)
##STR00194##
264 mg (1.42 mmol) of bis(trifluoromethyl)oxirane are added to a
solution of 300 mg (0.948 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one and 1.66 ml (1.66 mmol)
of 1 M sodium hydroxide in 5 mL of 1,4-dioxane. The reaction
mixture is heated in a Biotage microwave reactor at 130.degree. C.
for 2 hours. The reaction medium is evaporated to dryness and the
residue is taken up in EtOAc and washed with water and with
saturated NaCl. The organic phase is dried over magnesium sulfate
and evaporated to dryness. The residue is purified by
chromatography on silica gel (eluent: 95/5 DCM/MeOH) to give 250 mg
of (8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-(3,3,3-trif-
luoro-2-hydroxy-2-trifluoromethylpropyl)-8-trifluoromethyl-6,7,8,9-tetrahy-
dropyrimido[1,2-a]pyrimidin-4-one, the characteristics of which are
as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 497 tr (min)=0.71
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.81-1.95 (m,
2H), 2.21 (m, 1H), 2.44 (m, 1H), 2.95-3.36 (m, 3H), 3.47-3.64 (m,
2H), 3.69 (m, 1H), 4.08 (m, 1H), 4.57-5.05 (m, 4H), 5.40 (m, 1H),
8.74 (m, 1H).
EXAMPLE 49
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicyclo-
[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[-
1,2-a]pyrimidin-4-one (Compound 99)
##STR00195##
Step 49.1:
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trif-
luoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetic
acid
##STR00196##
95 mg (2.22 mmol) of lithium hydroxide monohydrate are added to a
solution of 720 mg (1.85 mmol) of methyl
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethy-
l-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate
(preparation described in Step 38.1) in 20 mL of THF/water (1/1:
v/v). The reaction mixture is stirred at room temperature for 2
hours, after which the THF is evaporated off and the solution is
acidified with 1 N HCl and extracted with EtOAc. The organic phase
is washed with water and with saturated NaCl, dried over magnesium
sulfate and then evaporated to dryness to give 690 mg of
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethy-
l-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetic acid, the
characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 375 tr (min)=1.63
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 1.81 (m, 2H),
2.02-2.18 (m, 1H), 2.32-2.43 (m, 1H), 3.10-3.32 (m, 3H), 3.49-3.59
(m, 1H), 3.68 (m, 1H), 3.98-4.08 (m, 1H), 4.24-4.35 (m, 1H),
4.37-4.47 (m, 1H), 4.57-4.86 (m, 4H), 12.71 (m, 1H).
Step 49.2:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-
-azabicyclo[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahyd-
ropyrimido[1,2-a]pyrimidin-4-one
##STR00197##
98 .mu.L (0.881 mmol) of N-methylmorpholine, 86 mg (0.44 mmol) of
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 69
mg (0.44 mmol) of 1-hydroxybenzotriazole hydrate are added to a
solution of 150 mg (0.4 mmol) of
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethy-
l-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetic acid in 10
mL of DMF. The reaction mixture is stirred for 10 minutes at room
temperature, followed by addition of 66 mg (0.44 mmol) of
(1R,5S)-3-oxa-8-azabicyclo[3.2.1]octane hydrochloride. The reaction
is continued at room temperature for 5 hours. The DMF is evaporated
off and the residue obtained is purified by chromatography on
silica gel (eluent: 95/5 DCM/MeOH) to give 130 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-[2-(3-oxa-8-azabicycl-
o[3.2.1]oct-8-yl)-2-oxoethyl]-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido-
[1,2-a]pyrimidin-4-one, the characteristics of which are as
follows:
LC/MS (method A): ESI+ [M+H]+: m/z 470 tr (min)=0.5
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6) performed at
140.degree. C.: 1.77-1.95 (m, 6H), 2.21-2.43 (m, 2H), 3.14-3.38 (m,
3H), 3.53-3.72 (m, 6H), 3.98 (d, 1H), 4.27-4.48 (m, 4H), 4.62 (s,
1H), 4.71 (s, 1H), 4.76 (s, 1H), 5.11 (d, 1H).
EXAMPLE 50
(8S)-9-(3-hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-
-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 50)
##STR00198##
430 .mu.L (1.29 mmol) of a 3 M solution of methylmagnesium bromide
in ethyl ether are added at 0.degree. C. to a solution of 173 mg
(0.43 mmol) of methyl
3-((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-tr-
ifluoromethyl-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)-propionate
(preparation described in Step 39.1) in 10 mL of THF. The reaction
medium is stirred at 0.degree. C. for 2 hours. 10 mL of saturated
ammonium chloride solution are added to the reaction medium. The
resulting mixture is extracted with ethyl acetate and the organic
phase is dried over magnesium sulfate and evaporated to dryness.
After purification by chromatography on silica gel (eluent: 95/5
DCM/MeOH), 128 mg of
(8S)-9-(3-hydroxy-3-methylbutyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept--
5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
are obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 403 tr (min)=0.53
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.09 (s, 3H),
1.12 (s, 3H), 1.64-1.76 (m, 2H), 1.78-1.87 (m, 2H), 2.02 (m, 1H),
2.33 (m, 1H), 3.13 (m, 1H), 3.24-3.35 (m, 2H), 3.63 (m, 1H), 3.69
(m, 1H), 4.12 (m, 1H), 4.20 (m, 1H), 4.25 (s, 1H), 4.53 (m, 1H),
4.59-5.03 (m, 4H).
EXAMPLE 51
(8S)-9-(1-hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hep-
t-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 104)
##STR00199##
146 mg (0.515 mmol) of titanium (IV) isopropoxide are added to a
solution of 200 mg (0.515 mmol) of methyl
((2S)-8-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-6-oxo-2-trifluoromethy-
l-3,4-dihydro-2H,6H-pyrimido[1,2-a]pyrimidin-1-yl)acetate
(preparation described in Step 38.1) in 3 mL of THF. The solution
is cooled to 0.degree. C., followed by dropwise addition of 858
.mu.L (2.58 mmol) of 3 M ethylmagnesium bromide in ethyl ether. The
reaction mixture is stirred for 30 minutes at room temperature. 10
mL of saturated ammonium chloride solution are added to the
reaction medium. The resulting mixture is extracted with ethyl
acetate and the organic phase is dried over magnesium sulfate and
evaporated to dryness. After purification by chromatography on
silica gel (eluent: 95/5 DCM/MeOH), 80 mg of
(8S)-9-(1-hydroxycyclopropylmethyl)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]he-
pt-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
are obtained, corresponding to the following characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 387 tr (min)=0.52
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 0.52-0.71 (m,
4H), 1.77-1.86 (m, 2H), 2.27 (m, 1H), 2.40 (m, 1H), 3.20-3.29 (m,
3H), 3.45 (d, 1H), 3.59 (m, 1H), 3.72 (m, 1H), 4.18 (m, 1H), 4.37
(m, 1H), 4.59-5.01 (m, 4H), 5.54 (s, 1H).
EXAMPLE 52
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8--
trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one
(Compound 106)
##STR00200##
Step 52.1: Quinolin-5-ylmethanol
##STR00201##
A suspension of 171 mg (4.49 mmol) of lithium aluminum hydride in
20 ml of THF is cooled to 0.degree. C. A solution of 700 mg (3.74
mmol) of methyl quinoline-5-carboxylate in 5 ml of THF is then
added dropwise. The reaction mixture is stirred at 0.degree. C. for
1 hour and then hydrolysed with, in this order, 0.17 ml of
H.sub.2O, 0.17 ml of NaOH and 3.times.0.17 ml of H.sub.2O. The
precipitate formed is filtered off and washed with THF and then
with EtOAc. The organic phase is washed with saturated NaCl
solution, dried and evaporated. After purification by
chromatography on silica gel (eluent: 95/5 DCM/MeOH), 190 mg of
quinolin-5-ylmethanol are obtained, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 160 tr (min)=0.43
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 4.97 (d, 2H),
5.40 (t, 1H), 7.51-7.65 (m, 2H), 7.72 (t, 1H), 7.93 (d, 1H), 8.53
(d, 1H), 8.88-8.93 (m, 1H).
Step 52.2: 5-chloromethylquinoline hydrochloride
##STR00202##
A solution of 190 mg (1.19 mmol) of quinolin-5-ylmethanol in 5 ml
of thionyl chloride is stirred for 10 minutes at room temperature
and then refluxed for 2 hours. The reaction mixture is evaporated,
the solid obtained is taken up in ethyl ether and the solution is
filtered, washed with ethyl ether and dried to give 255 mg of
5-chloromethylquinoline hydrochloride, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 178 tr (min)=1.07
.sup.1H NMR (300 MHz, .delta. in ppm, DMSO-d.sub.6): 5.40 (s, 2H),
7.96-8.10 (m, 3H), 8.34 (m, 1H), 9.17 (m, 1H), 9.27 (m, 1H).
Step 52.3:
(8S)-2-Chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-t-
etrahydropyrimido[1,2-a]pyrimidin-4-one
##STR00203##
A suspension of 180 mg (0.709 mmol) of
(8S)-2-chloro-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidi-
n-4-one and 693 mg (2.13 mmol) of cesium carbonate in 10 mL of
acetonitrile is stirred for 15 minutes at room temperature. 182 mg
(0.851 mmol) of 5-chloromethylquinoline hydrochloride are then
added, along with a catalytic amount of sodium iodide.
The reaction mixture is stirred at room temperature for 5 hours.
The crude product is evaporated and the residue is taken up in
water and extracted with ethyl acetate. The organic phase is dried
over magnesium sulfate and evaporated to dryness. The residue is
purified by chromatography on silica gel (eluent: 95/5 DCM/MeOH) to
give 160 mg of
(8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydrop-
yrimido[1,2-a]pyrimidin-4-one, corresponding to the following
characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 395 tr (min)=2.00
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6):
2.24-2.46 (m, 2H), 3.35-3.47 (m, 1H), 4.26-4.36 (m, 1H), 4.66-4.80
(m, 1H), 5.04 (d, 1H), 5.83 (d, 1H), 5.98 (s, 1H), 7.42 (d, 1H),
7.61 (m, 1H), 7.73 (t, 1H), 7.97 (d, 1H), 8.57 (d, 1H), 8.95 (m,
1H).
Step 52.4:
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5--
ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-on-
e
##STR00204##
160 mg (0.40 mmol) of
(8S)-2-chloro-9-quinolin-5-ylmethyl-8-trifluoromethyl-6,7,8,9-tetrahydrop-
yrimido[1,2-a]pyrimidin-4-one and 82 mg (0.60 mmol) of
(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride are mixed
together. The powder obtained is placed in a tube and 158 .mu.L
(1.13 mmol) of triethylamine are added. The tube is sealed and
heated at 130.degree. C. in an oil bath for 7 hours. The crude
product obtained is taken up in DCM and the organic phase is washed
with water, dried over magnesium sulfate and then evaporated to
dryness. The residue is purified by chromatography on silica gel
(eluent: 95/5 DCM/MeOH) to give 125 mg of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-9-quinolin-5-ylmethyl-8-
-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one,
the characteristics of which are as follows:
LC/MS (method A): ESI+ [M+H]+: m/z 458 tr (min)=0.47
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.42-1.67 (bm,
2H), 2.29-2.46 (m, 2H), 2.74-3.20 (bm, 4H), 3.27-3.36 (m, 1H), 4.27
(m, 2H), 4.42 (m, 1H), 4.52-4.80 (bm, 2H), 4.85 (m, 1H), 5.91 (d,
1H), 7.39 (d, 1H), 7.56 (m, 1H), 7.71 (t, 1H), 7.93 (d, 1H), 8.62
(m, 1H), 8.92 (m, 1H).
EXAMPLE 53
(S)-9-[2-(6-difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-azabi-
cyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a]p-
yrimidin-4-one (Compound 114)
##STR00205##
Step 53.1: 5-bromo-2-difluoromethoxypyridine
##STR00206##
5.42 g (34.48 mmol) of sodium chlorodifluoroacetate are added to a
solution of 5 g (28.74 mmol) of 5-bromo-1H-pyrid-2-one in 120 ml of
acetonitrile, under argon.
The white suspension obtained is refluxed overnight and then
evaporated to dryness. The residue is taken up in aqueous ammonium
chloride solution and extracted with EtOAc. The organic phase is
dried over magnesium sulfate and then evaporated to dryness. The
crude product is purified by chromatography on silica gel (eluent:
0/100 EtOAc/heptane to 20/80 EtOAc/heptane over 35 minutes) to give
2.2 g of 5-bromo-2-difluoromethoxypyridine, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 226 tr (min)=2.08
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 7.12
(d, 1H), 7.67 (t, 1H), 8.15 (dd, 1H), 8.43 (d, 1H).
Step 53.2: 5-(1-butoxyvinyl)-2-difluoromethoxypyridine
##STR00207##
1 g (4.46 mmol) of 5-bromo-2-difluoromethoxypyridine in 20 mL of
H.sub.2O/DMF (1/4: v/v), 1.46 mL (11.16 mmol) of N-butyl vinyl
ether, 30.68 mg (0.13 mmol) of palladium(II) acetate, 125 mg (0.29
mmol) of 1,3-bis(diphenylphosphino)propane and 746 mg (5.36 mmol)
of potassium carbonate are placed in a microwave tube. After
microwave irradiation for 1 hour at 120.degree. C., the crude
product is taken up in water and extracted with DCM. The organic
phase is dried over magnesium sulfate and then evaporated to
dryness. The crude product is purified by chromatography on silica
gel (eluent: 0/100 EtOAc/heptane to 20/80 EtOAc/heptane over 35
minutes) to give 110 mg of
5-(1-butoxyvinyl)-2-difluoromethoxypyridine, corresponding to the
following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 244 tr (min)=2.74
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 0.94
(t, 3H), 1.38-1.53 (m, 2H), 1.66-1.78 (m, 2H), 3.86 (t, 2H), 4.38
(d, 1H), 4.85 (d, 1H), 7.09 (d, 1H), 7.71 (t, 1H), 8.09 (dd, 1H),
8.49 (d, 1H).
Step 53.3: 2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone
##STR00208##
A solution of 100 mg (0.41 mmol) of
5-(1-butoxyvinyl)-2-difluoromethoxypyridine in 4 mL of THF/H.sub.2O
(3/1: v/v) is cooled to 0.degree. C. 74 mg (0.41 mmol) of
N-bromosuccinimide are then added in a single portion. The yellow
solution is stirred at 0.degree. C. for 1 hour and then taken up in
water and extracted with EtOAc. The organic phase is washed with
saturated aqueous NaHCO.sub.3 solution and then with saturated NaCl
solution, dried over magnesium sulfate and then evaporated to
dryness. The crude product is purified by chromatography on silica
gel (eluent: 20/80 EtOAc/heptane to 40/60 EtOAc/heptane over 15
minutes) to give 82 mg of
2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone, corresponding to
the following characteristics:
LC/MS (method G): ESI+ [M+H]+: m/z 266 tr (min)=1.84
.sup.1H NMR spectrum (300 MHz, .delta. in ppm, DMSO-d.sub.6): 4.91
(s, 2H), 7.19 (d, 1H), 7.75 (t, 1H), 8.36 (dd, 1H), 8.85 (d,
1H).
Step 53.4:
(8S)-9-[2-(6-difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-
-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyri-
mido[1,2-a]pyrimidin-4-one
##STR00209##
The procedure used is the same as that of step 12.3.
120 mg (0.38 mmol) of
(8S)-2-(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8-
,9-tetrahydropyrimido[1,2-a]pyrimidin-4-one, 371 mg (1.42 mmol) of
cesium carbonate, 121 mg (0.45 mmol) of
2-bromo-1-(6-difluoromethoxypyrid-3-yl)ethanone and 15 mL of
acetonitrile were used in the reaction. After purification by
chromatography on silica gel (eluent A/B: DCM/MeOH, gradient A/B: t
0 min 0% B, t 25 min 10% B, t 30 min 10% B), 38 mg of
(8S)-9-[2-(6-difluoromethoxypyrid-3-yl)-2-oxoethyl]-2-(1S,4S)-2-oxa-5-aza-
bicyclo[2.2.1]hept-5-yl-8-trifluoromethyl-6,7,8,9-tetrahydropyrimido[1,2-a-
]pyrimidin-4-one were obtained, corresponding to the following
characteristics:
LC/MS (method A): ESI+ [M+H]+: m/z 502 tr (min)=0.67
.sup.1H NMR (600 MHz, .delta. in ppm, DMSO-d.sub.6): 1.56-1.74 (m,
2H), 2.21 (m, 1H), 2.44 (m, 1H), 2.78-3.09 (m, 3H), 3.23 (m, 1H),
3.47-3.85 (m, 1H), 4.37 (m, 1H), 4.41-4.53 (m, 2H), 4.53-4.71 (m,
3H), 5.66-5.78 (m, 1H), 7.26 (d, 1H), 7.82 (t, 1H), 8.48 (dd, 1H),
9.01 (m, 1H).
The table which follows illustrates the chemical structures and the
physical properties of some examples of compounds according to the
invention. In this table: in the "Salt" column, "-" represents a
compound in free base form, whereas "HCl" represents a compound in
hydrochloride form; the "Data" column successively indicates the
LC/MS analytical method used (A, B, C or F) and detailed in the
experimental section, the retention time (tr) of the compound
expressed in minutes, and the peak [M+H].sup.+ identified by mass
spectrometry.
TABLE-US-00001 TABLE (I) ##STR00210## No. n Y R.sub.1 L Salt Data 1
Ex. 13 1 ##STR00211## ##STR00212## *--C(CH.sub.3).sub.2--CH.sub.2--
-- Method B: tr (min) = 0.53 [M + H]+: 450 2 Ex. 27 1 ##STR00213##
##STR00214## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.50 [M +
H]+: 436 3 1 ##STR00215## ##STR00216## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.38 [M + H]+: 451 4 Ex. 28 1 ##STR00217##
##STR00218## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.49 [M +
H]+: 450 5 Ex. 42 1 ##STR00219## ##STR00220## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.41 [M + H]+: 465 6 Ex. 25 1 ##STR00221##
##STR00222## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.48 [M +
H]+: 479 7 Ex. 6 1 ##STR00223## ##STR00224## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.51 [M + H]+: 436 8 0 ##STR00225##
##STR00226## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.49 [M +
H]+: 479 9 Ex. 43 0 ##STR00227## ##STR00228## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.42 [M + H]+: 465 10 0 ##STR00229##
##STR00230## *--CH.sub.2--CH.sub.2-- -- * Method C: tr (min) = 1.19
[M + H]+: 451 11 0 ##STR00231## ##STR00232## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.38 [M + H]+: 451 12 Ex. 31 1 ##STR00233##
##STR00234## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.39
[M + H]+: 422 13 0 ##STR00235## ##STR00236##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.39 [M + H]+: 422
14 Ex. 41 1 ##STR00237## ##STR00238## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.40 [M + H]+: 495 15 Ex. 3 1 ##STR00239##
##STR00240## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.51 [M +
H]+: 450 16 Ex. 7 0 ##STR00241## ##STR00242## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.52 [M + H]+: 450 17 Ex. 29 0 ##STR00243##
##STR00244## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.49 [M +
H]+: 450 18 0 ##STR00245## ##STR00246## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.48 [M + H]+: 450 19 Ex. 9 1 ##STR00247##
##STR00248## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.48 [M +
H]+: 450 20 Ex. 12 1 ##STR00249## ##STR00250## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.50 [M + H]+: 450 21 Ex. 30 0 ##STR00251##
##STR00252## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.51 [M +
H]+: 436 22 1 ##STR00253## ##STR00254## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.45 [M + H]+: 491 23 Ex. 14 1 ##STR00255##
##STR00256## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.60
[M + H]+: 507 24 Ex. 15 0 ##STR00257## ##STR00258##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.60 [M + H]+: 507
25 Ex. 2 1 ##STR00259## ##STR00260## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.55 [M + H]+: 442 26 Ex. 8 0 ##STR00261##
##STR00262## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.56
[M + H]+: 442 27 1 ##STR00263## ##STR00264##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.46 [M + H]+: 439
28 0 ##STR00265## ##STR00266## *--CH.sub.2--CH.sub.2-- -- Method A:
tr (min) = 0.45 [M + H]+: 439 29 Ex. 26 1 ##STR00267## ##STR00268##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.67 [M + H]+: 415 30 0
##STR00269## ##STR00270## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.67 [M + H]+: 415 31 1 ##STR00271## ##STR00272## *--CO--CH.sub.2--
-- Method A: tr (min) = 0.42 [M + H]+: 465 32 0 ##STR00273##
##STR00274## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.48
[M + H]+: 436 33 1 ##STR00275## ##STR00276## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.67 [M + H]+: 504 34 1 ##STR00277##
##STR00278## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.47 [M +
H]+: 509 35 1 ##STR00279## ##STR00280## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.67 [M + H]+: 480 36 1 ##STR00281## ##STR00282##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.43 [M + H]+: 479 37 1
##STR00283## ##STR00284## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.69 [M + H]+: 501 38 Ex. 16 1 ##STR00285## ##STR00286##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.49 [M + H]+: 439 39 1
##STR00287## ##STR00288## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.52 [M + H]+: 440 40 1 ##STR00289## ##STR00290## *--CO--CH.sub.2--
-- Method A: tr (min) = 0.68 [M + H]+: 471 41 1 ##STR00291##
##STR00292## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.64 [M +
H]+: 520 42 1 ##STR00293## ##STR00294## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.62 [M + H]+: 460 43 Ex. 10 1 ##STR00295##
##STR00296## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.55 [M +
H]+: 456 44 1 ##STR00297## ##STR00298## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.61 [M + H]+: 470 45 Ex. 32 1 ##STR00299##
##STR00300## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.61 [M +
H]+: 466 46 1 ##STR00301## ##STR00302## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.55 [M + H]+: 440 47 Ex. 17 1 ##STR00303##
##STR00304## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.64 [M +
H]+: 493 48 Ex. 1 1 ##STR00305## ##STR00306## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.68 [M + H]+: 471 49 Ex. 39 1 ##STR00307##
##STR00308## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.63
[M + H]+: 431 50 Ex. 50 1 ##STR00309## ##STR00310##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.53 [M + H]+: 403
51 Ex. 18 1 ##STR00311## ##STR00312## *--CH.sub.2-- -- Method A: tr
(min) = 0.68 [M + H]+: 461 52 Ex. 19 1 ##STR00313## ##STR00314##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.65 [M + H]+: 507 53 Ex.
4 1 ##STR00315## ##STR00316## *--CO--CH.sub.2-- -- Method A: tr
(min) = 0.58 [M + H]+: 454 54 Ex. 38 1 ##STR00317## ##STR00318##
*--CH.sub.2-- -- Method A: tr (min) = 0.63 [M + H]+: 417 55 1
##STR00319## ##STR00320## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.61 [M + H]+: 460 56 Ex. 5 1 ##STR00321## ##STR00322##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.60 [M + H]+: 401 57 Ex.
21 1 ##STR00323## ##STR00324## *--CO--CH.sub.2-- -- Method A: tr
(min) = 0.60 [M + H]+: 523 58 1 ##STR00325## ##STR00326##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.55 [M + H]+: 509 59 1
##STR00327## ##STR00328## *--CH.sub.2-- -- Method C tr (min) = 0.85
[M + H]+: 413 60 1 ##STR00329## ##STR00330## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.62 [M + H]+: 504 61 1 ##STR00331##
##STR00332## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.64 [M +
H]+: 493 62 Ex. 11 1 ##STR00333## ##STR00334## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.52 [M + H]+: 443 63 Ex. 33 1 ##STR00335##
##STR00336## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.62 [M +
H]+: 498 64 1 ##STR00337## ##STR00338## *--CO--CH.sub.2-- -- Method
A: tr (min) = 0.65 [M + H]+: 515 65 1 ##STR00339## ##STR00340##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.63 [M + H]+: 466 66 1
##STR00341## ##STR00342## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.40 [M + H]+: 439 67 1 ##STR00343## ##STR00344## *--CO--CH.sub.2--
-- Method C tr (min) = 0.88 [M + H]+: 399 68 Ex. 40 1 ##STR00345##
##STR00346## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.59 [M +
H]+: 436 69 Ex. 20 1 ##STR00347## ##STR00348## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.54 [M + H]+: 439 70 Ex. 37 0 ##STR00349##
##STR00350## *--CH.sub.2--CH.sub.2-- -- Method B: tr (min) = 0.69
[M + H]+: 536 71 Ex. 34 1 ##STR00351## ##STR00352##
*--CHOH--CH.sub.2-- OH abs. conf. (S) -- Method B: tr (min) = 0.71
[M + H]+: 499 72 Ex. 35 0 ##STR00353## ##STR00354##
*--CH.sub.2--CH.sub.2-- -- Method B: tr (min) = 0.68 [M + H]+: 451
73 1 ##STR00355## ##STR00356## *--CO--CH.sub.2-- -- Method F tr
(min) = 0.84 [M + H]+: 449 74 Ex. 36 0 ##STR00357## ##STR00358##
*--CH.sub.2--CH.sub.2-- HCl Method B: tr (min) = 0.56 [M + H]+: 522
75 Ex. 23 1 ##STR00359## ##STR00360## *--CO--CH.sub.2-- -- Method
B: tr (min) = 0.55 [M + H]+: 450 76 0 ##STR00361## ##STR00362##
*--CH.sub.2--CH.sub.2-- -- Method C tr (min) = 1.26 [M + H]+: 465
77 0 ##STR00363## ##STR00364## *--CH.sub.2--CH.sub.2-- -- Method B:
tr (min) = 82 [M + H]+: 449 78 0 ##STR00365## ##STR00366##
*--CH.sub.2--CH.sub.2-- HCl Method B: tr (min) = 0.58 [M + H]+: 536
79 0 ##STR00367## ##STR00368## *--CHOH--CH.sub.2-- OH abs. conf.
(S) -- Method B: tr (min) = 0.65 [M + H]+: 451 80 Ex. 24 1
##STR00369## ##STR00370## *--CHOH--CH.sub.2-- OH abs. conf. (S) --
Method B: tr (min) = 0.68 [M + H]+: 451 81 1 ##STR00371##
##STR00372## *--CH.sub.2--CH.sub.2-- -- Method B: tr (min) = 0.81
[M + H]+: 465
82 1 ##STR00373## ##STR00374## *--CHOH--CH.sub.2-- OH abs. conf.
(R) -- Method B: tr (min) = 0.85 [M + H]+: 507 83 1 ##STR00375##
##STR00376## *--CH.sub.2--CH.sub.2-- -- Method B: tr (min) = 0.68
[M + H]+: 451 84 Ex. 22 1 ##STR00377## ##STR00378##
*--CH.sub.2--CH.sub.2-- -- Method B: tr (min) = 0.85 [M + H]+: 449
85 1 ##STR00379## ##STR00380## *--CO--CH.sub.2-- -- Method B: tr
(min) = 0.52 [M + H]+: 450 86 1 ##STR00381## ##STR00382##
*--CH.sub.2-- -- Method F tr (min) = 0.83 [M + H]+: 461 87 1
##STR00383## ##STR00384## *--CO--CH.sub.2-- -- Method F tr (min) =
0.83 [M + H]+: 450 88 1 ##STR00385## ##STR00386## *--CO--CH.sub.2--
-- Method F tr (min) = 1.01 [M + H]+: 450 89 1 ##STR00387##
##STR00388## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.55
[M + H]+: 470 90 Ex. 44 1 ##STR00389## ##STR00390##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.54 [M + H]+: 456
91 1 ##STR00391## ##STR00392## *--CO--CH.sub.2-- -- Method A: tr
(min) = 0.62 [M + H]+: 514 92 Ex. 45 1 ##STR00393## ##STR00394##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.61 [M + H]+: 429
93 Ex. 46 1 ##STR00395## ##STR00396## *--CH.sub.2-- -- Method A: tr
(min) = 0.57 [M + H]+: 415 94 1 ##STR00397## ##STR00398##
*--CH.sub.2-- -- Method D tr (min) = 0.84 [M + H]+: 456 95 Ex. 47 1
##STR00399## ##STR00400## *--CH.sub.2-- -- Method D tr (min) = 1.01
[M + H]+: 450 96 Ex. 48 1 ##STR00401## ##STR00402## *--CH.sub.2--
-- Method A: tr (min) = 0.71 [M + H]+: 497 97 1 ##STR00403##
##STR00404## *--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.68
[M + H]+: 511 98 1 ##STR00405## ##STR00406## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.51 [M + H]+: 470 99 Ex. 49 1 ##STR00407##
##STR00408## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.5 [M +
H]+: 470 100 1 ##STR00409## ##STR00410## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.6 [M + H]+: 429 101 1 ##STR00411##
##STR00412## *--CH.sub.2-- -- Method D tr (min) = 0.95 [M + H]+:
415 102 1 ##STR00413## ##STR00414## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.68 [M + H]+: 455 103 1 ##STR00415##
##STR00416## *--CH.sub.2-- -- Method D tr (min) = 1.13 [M + H]+:
441 104 Ex. 51 1 ##STR00417## ##STR00418## *--CH.sub.2-- -- Method
A: tr (min) = 0.52 [M + H]+: 387 105 1 ##STR00419## ##STR00420##
*--CH.sub.2--CH.sub.2-- -- Method A: tr (min) = 0.53 [M + H]+: 401
106 Ex. 52 1 ##STR00421## ##STR00422## *--CH.sub.2-- -- Method A:
tr (min) = 0.47 [M + H]+: 458 107 1 ##STR00423## ##STR00424##
*--CO--CH.sub.2-- -- Method A: tr (min) = 0.57 [M + H]+: 456 108 1
##STR00425## ##STR00426## *--CO--CH.sub.2-- -- Method A: tr (min) =
0.54 [M + H]+: 513 109 1 ##STR00427## ##STR00428## *--CH.sub.2-- --
Method A: tr (min) = 0.53 [M + H]+: 458 110 1 ##STR00429##
##STR00430## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.56 [M +
H]+: 444 111 1 ##STR00431## ##STR00432## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.49 [M + H]+: 550 112 1 ##STR00433##
##STR00434## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.53 [M +
H]+: 418 113 1 ##STR00435## ##STR00436## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.38 [M + H]+: 475 114 Ex. 53 1 ##STR00437##
##STR00438## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.67 [M +
H]+: 502 115 1 ##STR00439## ##STR00440## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.61 [M + H]+: 564 116 1 ##STR00441##
##STR00442## *--CH.sub.2-- -- Method A: tr (min) = 0.67 [M + H]+:
479 117 1 ##STR00443## ##STR00444## *--CH.sub.2--CH.sub.2-- --
Method A: tr (min) = 0.49 [M + H]+: 508 118 1 ##STR00445##
##STR00446## *--CO--CH.sub.2-- -- Method A: tr (min) = 0.79 [M +
H]+: 567 119 1 ##STR00447## ##STR00448## *--CO--CH.sub.2-- --
Method A: tr (min) = 0.48 [M + H]+: 484
The compounds according to the invention underwent pharmacological
trials to determine their inhibitory effect on the growth of
Plasmodium falciparum.
Antimalarial Activity Test
The compounds according to the invention underwent pharmacological
trials to determine their inhibitory effect on the growth of
Plasmodium falciparum (strain NF54 sensitive to inhibition with
chloroquine) in an in vitro test using infected human erythrocytes.
The growth of the parasites is measured via the incorporation of
tritiated hypoxanthine compared with the incorporation in the
absence of drug. The tests are performed in 96-well microplates
(Falcon.TM. 96-well microtiter plates, ref. No. 353072) in RPMI
1640 solutions (10.44 g/l) (without hypoxanthine) with HEPES (5.94
g/l), NaHCO.sub.3 (2.1 g/l), neomycin (100 g/mL)+AlbumaxR II (5
g/l) supplemented with human erythrocytes with a final hematocrit
of 1.25% and a final parasitemia of 0.15%.
The stock solution of the compounds is prepared at 10 mg/mL in
DMSO. For the test, fresh solutions at the desired concentrations
are prepared in RPMI medium. For the test, 100 .mu.l of compound
are mixed with 100 .mu.l of infected blood. For the determination
of the IC.sub.50 values, the compounds are tested in twofold serial
dilution.
The plates are incubated at 37.degree. C. under a humid atmosphere
with 93% N.sub.2, 4% CO.sub.2 and 3% O.sub.2. After 48 hours, 50
.mu.l of .sup.3H-hypoxanthine (=0.5 .mu.Ci) in RPMI medium are
added to each well and incubation is continued for a further 24
hours. Next, the plates are washed with distilled water and the
cell lyzate is transferred onto fiberglass filters. The filters are
dried and the radioactivity is determined by liquid scintillation.
The results in cpm are converted into percentages of inhibition.
The inhibitory activity is given by the concentration that inhibits
50% of the growth of the parasite relative to a control without
compound.
The IC.sub.50 values are between 3 nM and 4000 nM, in particular
between 3 nM and 384 nM and even more particularly less than or
equal to 200 nM.
The table of results for the antimalarial activity test is given
below:
TABLE-US-00002 IC.sub.50 Plasmodium Compound falciparum No. NF54 1
20 nM 2 15 nM 3 13 nM 4 58 nM 5 95 nM 6 >200 nM 7 10 nM 8
>200 nM 9 >200 nM 10 11 nM 11 40 nM 12 9 nM 13 21 nM 14 70 nM
15 150 nM 16 >200 nM 17 160 nM 18 93 nM 19 24 nM 20 35 nM 21 82
nM 22 >200 nM 23 3 nM 24 8 nM 25 <3.4 nM 26 10 nM 27 <4.5
nM 28 9 nM 29 46 nM 30 >240 nM 31 75 nM 32 4 nM 33 4000 nM 34
>200 nM 35 >210 nM 36 240 nM 37 230 nM 38 140 nM 39 98 nM 40
80 nM 41 930 nM 42 80 nM 43 42 nM 44 106 nM 45 112 nM 46 398 nM 47
13 nM 48 27 nM 49 6 nM 50 8 nM 51 65 nM 52 130 nM 53 870 nM 54 10
nM 55 28 nM 56 45 nM 57 65 nM 58 53 nM 59 87 nM 60 19 nM 61 130 nM
62 11 nM 63 384 nM 64 39 nM 65 21 nM 66 73 nM 67 43 nM 68 27 nM 69
96 nM 70 12 nM 71 23 nM 72 37 nM 73 44 nM 74 68 nM 75 80 nM 76 93
nM 77 160 nM 78 360 nM 79 640 nM 82 9 nM 83 10 nM 84 110 nM 85 150
nM 86 170 nM 88 140 nM 89 3.4 nM 90 2 nM 91 25 nM 92 4 nM 93 4 nM
94 9 nM 95 7 nM 96 170 nM 97 30 nM 98 140 nM 99 170 nM 100 9 nM 101
10 nM 102 5 nM 103 75 nM 104 12 nM 105 24 nM 106 13 nM 107 100 nM
108 86 nM 109 79 nM 110 330 nM 111 5 nM 112 200 nM 113 430 nM 114
245 nM 115 3 nM 116 117 nM 117 6 nM 118 15 nM 119 30 nM
Human PI3K.alpha. Activity Test
The compounds according to the invention underwent pharmacological
trials to measure the selectivity toward human lipid kinases and
especially human PI3K.alpha.. The test uses a luciferin/luciferase
system to measure the concentration of ATP and its consumption
during the enzymatic reaction. The test is performed in 96-well
format (Corning/Costar 96 black flat-bottomed half-wells plate,
ref. 3694) in a total volume of 30 .mu.l.
To 1 .mu.l of inhibitor in 100% DMSO are added (final
concentrations) 50 .mu.M of the substrate PIP2
((L-.alpha.-phosphatidyl-D-myoinositol 4,5-bisphosphate, Calbiochem
524644), 2 .mu.M of ATP and 1.7 .mu.g/mL of
PI3K.alpha.(p110.alpha./p85.alpha., Invitrogen PV4788) in a buffer
of Tris/HCl 50 mM pH 7.5, EGTA 1 mM, MgCl.sub.2 10 mM, Chaps 0.03%,
1 mM DTT). After 90 minutes, the reaction is quenched by adding 20
.mu.l/well of KinaseGlo reagent (Promega V6713). After 10 minutes
in the dark, the luminescence is read using a PHERAStar microplate
reader (reading at 0.8 sec/well).
The IC.sub.50 values are determined by the preparation of
successive threefold dilutions on at least a scale of more than 10
000. The IC.sub.50 values are between 190 nM and more than 10 000
nM, in particular between 1040 nM and more than 10 000 nM and even
more particularly greater than 2000 nM.
The activity of the other isoforms of human PI3K may be measured in
the same manner.
The table of results for the activity of human PI3K.alpha. test is
given below:
TABLE-US-00003 IC.sub.50 No. Human PI3K.alpha. 1 3130 nM 2 10000 nM
3 7200 nM 4 >10000 nM 5 8200 nM 6 >10000 nM 7 10000 nM 8
>10000 nM 9 >10000 nM 10 7200 nM 11 10000 nM 12 2900 nM 13
5750 nM 14 >10000 nM 15 >7200 nM 16 >7200 nM 17 10000 nM
18 >10000 nM 19 >10000 nM 20 >10000 nM 21 >10000 nM 22
>10000 nM 23 1040 nM 24 2440 nM 25 1000 nM 26 2000 nM 27 1530 nM
28 2260 nM 29 7930 nM 30 >10000 nM 31 6350 nM 32 3700 nM 33
>10000 nM 34 >10000 nM 35 >10000 nM 36 >10000 nM 37
>10000 nM 38 5770 nM 39 >10000 nM 40 >10000 nM 41 4200 nM
42 >10000 nM 43 >10000 nM 44 >10000 nM 45 >10000 nM 46
>10000 nM 47 >10000 nM 48 >10000 nM 49 2740 nM 50 4300 nM
51 >10000 nM 52 >10000 nM 53 >10000 nM 54 2210 nM 55
>10000 nM 56 >10000 nM 57 >10000 nM 58 6400 nM 59
>10000 nM 60 >10000 nM 61 >10000 nM 62 >10000 nM 63
>7200 nM 64 >10000 nM 65 >10000 nM 66 >10000 nM 67 4000
nM 68 6600 nM 69 >10000 nM 70 1000 nM 71 810 nM 72 730 nM 73
2500 nM 74 820 nM 75 10000 nM 76 950 nM 77 820 nM 78 250 nM 79 1600
nM 80 1600 nM 81 2000 nM 82 340 nM 83 190 nM 84 200 nM 85 >10000
nM 86 7300 nM 87 10000 nM 88 1300 nM 89 2800 nM 90 2400 nM 91
>10000 nM 92 450 nM 93 780 nM 94 130 nM 95 180 nM 96 8500 nM 97
440 nM 98 >10000 nM 99 >10000 nM 100 1980 nM 101 450 nM 102
2500 nM 103 840 nM 104 930 nM 105 1900 nM 106 >10000 nM 107
>10000 nM 108 >10000 nM 109 7800 nM 110 >10000 nM 111 330
nM 112 >10000 nM 113 >10000 nM 114 >10000 nM 115 590 nM
116 >10000 nM 117 380 nM 118 >10000 nM 119 >10000 nM
The table below shows the human PI3K.alpha. activity test results
for known compounds derived from the applications mentioned above
WO 2011/001 112 and WO 2011/001 113.
TABLE-US-00004 IC.sub.50 COM- Human POUNDS STRUCTURE PI3K.alpha.
Example 1 (p. 39, WO 2011/001 112) ##STR00449## 15 nM Example 10
(p. 61, WO 2011/001 112) ##STR00450## 17 nM Example 5 (p. 54, WO
2011/001 113) ##STR00451## 6 nM Example 1 (p. 44, WO 2011/001 113)
##STR00452## 9 nM
It may be seen that although the compounds of the present invention
are derived from inhibitors of human PI3K and in particular PI3K,
such compounds no longer inhibit, or only sparingly inhibit, this
class of human kinases. Thus, they are clearly distinguished from
the already-known CF3 pyrimidinones, described in patent
applications WO 2011/001 112 and WO 2011/001 113, which are
powerful inhibitors of human PI3K.alpha., which may be used for the
treatment of malaria but above all for various cancers in man.
Similar kinomes are present in all species of Plasmodium, such as
P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi. The
compounds of the invention may thus be useful in the treatment of
malaria induced by all the parasites mentioned above. In addition,
these kinases are found in other parasites, such as Trypanosoma
(for example T. brucei, T. cruzei) and Leishmania (for example L.
major, L. donovani). The compounds of the invention may thus be
used in the treatment of sleeping sickness, Chagas disease, the
various forms of leishmaniasis and other parasitic infections.
The compounds according to the invention may thus be used for the
preparation of medicaments, in particular medicaments for
inhibiting parasite growth.
Thus, according to another of its aspects, a subject of the
invention is medicaments that comprise a compound of formula (I),
or an addition salt of the compound of formula (I) with a
pharmaceutically acceptable acid or base.
These medicaments find their use in therapeutics, especially in the
treatment of malaria induced by all species of Plasmodium such as
P. falciparum, P. vivax, P. malariae, P. ovale and P. knowlesi, but
also induced by other species of parasites, for instance
Trypanosoma such as T. brucei, T. cruzei and Leishmania, for
instance L. major, L. donovani.
These medicaments also find their use in therapeutics in the
treatment of sleeping sickness, Chagas disease, the various forms
of leishmaniasis and infections such as schistosomiasis
(bilharzia), toxoplasmosis and coccidiosis which are caused by
other parasites, respectively schistosomes, toxoplasma and
Eimeria.
According to another of its aspects, the present invention relates
to pharmaceutical compositions comprising, as active ingredient, a
compound according to the invention. These pharmaceutical
compositions contain an effective dose of at least one compound
according to the invention, or a pharmaceutically acceptable salt
of said compound, and also at least one pharmaceutically acceptable
excipient.
Said excipients are chosen, according to the pharmaceutical form
and the mode of administration desired, from the usual excipients
which are known to those skilled in the art.
In the pharmaceutical compositions of the present invention for
oral, sublingual, subcutaneous, intramuscular, intravenous,
topical, local, intratracheal, intranasal, transdermal or rectal
administration, the active ingredient of formula (I) above, or its
salt, can be administered in unit administration form, as a mixture
with conventional pharmaceutical excipients, to animals or to human
beings for the treatment of the above disorders or diseases.
The appropriate unit administration forms include oral-route forms
such as tablets, soft or hard gel capsules, powders, granules and
oral solutions or suspensions, sublingual, buccal, intratracheal,
intraocular and intranasal administration forms, inhalation forms,
topical, transdermal, subcutaneous, intramuscular or intravenous
administration forms, rectal administration forms and implants. For
topical application, the compounds according to the invention can
be used in creams, gels, ointments or lotions.
By way of example, a unit administration form of a compound
according to the invention in tablet form may comprise the
following components:
TABLE-US-00005 Compound according to the invention 50.0 mg Mannitol
223.75 mg Croscaramellose sodium 6.0 mg Corn starch 15.0 mg
Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg
There may be particular cases where higher or lower dosages are
appropriate; such dosages do not depart from the context of the
invention. According to the usual practice, the dosage appropriate
for each patient is determined by the physician according to the
method of administration and the weight and response of said
patient.
According to another of its aspects, the present invention also
relates to a method for treating the pathological conditions
indicated above, which comprises the administration, to a patient,
of an effective dose of a compound according to the invention, or a
pharmaceutically acceptable salt thereof.
* * * * *